Bi-specific anti-CGRP receptor/PAC1 receptor antigen binding proteins and uses thereof

ABSTRACT

The present invention relates to bispecific antigen binding proteins that are capable of binding to both the human CGRP receptor and the human PAC1 receptor. Pharmaceutical compositions comprising the bispecific antigen binding proteins as well as methods for producing them are also disclosed. Methods of using the bispecific antigen binding proteins to ameliorate or treat conditions associated with the two receptors, such as chronic pain, migraine, and cluster headache, are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/050,737, filed Sep. 15, 2014, which is hereby incorporated byreference in its entirety.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The present application contains a Sequence Listing, which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. The computer readable format copy of theSequence Listing, which was created on Sep. 8, 2015, is namedA-1922-WO-PCT_ST25.txt and is 1,091 kilobytes in size.

FIELD OF THE INVENTION

The present invention relates to the field of biopharmaceuticals. Inparticular, the invention relates to bispecific antigen binding proteinsthat are capable of specifically binding to human calcitoningene-related peptide (CGRP) receptor and human pituitary adenylatecyclase-activating polypeptide type I (PAC1) receptor, pharmaceuticalcompositions comprising the bispecific antigen binding proteins, andmethods of producing and using such bispecific antigen binding proteins.

BACKGROUND OF THE INVENTION

Migraine is a complex, common neurological condition that ischaracterized by severe, episodic attacks of headache and associatedfeatures, which may include nausea, vomiting, sensitivity to light,sound or movement. In some patients, the headache is preceded oraccompanied by sensory warning signs or symptoms (i.e. auras). Theheadache pain may be severe and may also be unilateral in certainpatients. Migraine attacks are disruptive to daily life and costbillions of dollars each year in missed work days and impairedperformance (Modi and Lowder, Am. Fam. Physician, Vol. 73:72-78, 2006).

Migraine is a highly prevalent disease worldwide with approximately 15%of the European population and 12% of the United States populationsuffering from migraine attacks (Lipton et al, Neurology, Vol.68:343-349, 2007). Additionally, migraines have been found to beassociated with a number of psychiatric and medical comorbidities suchas depression and vascular disorders (Buse et al., Neurol. Neurosurg.Psychiatry, Vol. 81:428-432, 2010; Bigal et al., Neurology, Vol.72:1864-1871, 2009).

Migraine headache is commonly treated acutely, primarily with analgesicsand a class of drugs called triptans (Humphrey et al. Ann NY Acad Sci.,Vol. 600:587-598, 1990; Houston and Vanhoutte, Drugs, Vol. 31:149-1631986). The triptans, which are selective serotonin 5-HT1B/1D agonists,are effective drugs for acute migraine and are generally well tolerated,but are contraindicated in the presence of cardiovascular disease due totheir potential for coronary vasoconstriction. In addition, manymigraine patients do not respond favorably to triptans. In ameta-analysis of 53 trials, up to a third of all people with migraineand 40% of all migraine attacks did not respond to triptans (Ferrari etal., Lancet, Vol. 358:1668-1675, 2001).

Migraine prophylaxis is an area of large unmet medical need.Approximately 40% of the migraine patient population would benefit frompreventive therapy (Lipton et al., Neurology, Vol. 68:343-349, 2007).However, only approximately 12% of patients receive any preventivetherapy due in part to limited efficacy and significant tolerability andsafety issues with available preventive therapies. Topiramate, ananticonvulsant that blocks voltage-dependent sodium channels and certainglutamate receptors (AMPA-kainate), is the medication most often usedfor migraine prophylaxis in the United States. Topiramate is the onlymigraine prophylactic agent with demonstrated efficacy in both episodicand chronic migraine patients through randomized placebo-controlledtrials (Diener et al., Cephalalgia, Vol. 27:814-823, 2007; Silbersteinet al., Headache, Vol. 47:170-180, 2007). However, approximately 50% ofpatients fail to respond to topiramate and it is poorly tolerated.Common adverse events associated with topiramate treatment includeparesthesia, anorexia, and cognitive adverse events, includingpsychomotor slowing, somnolence, language difficulties, and difficultieswith memory and concentration (Brandes et al., JAMA, Vol. 291:965-973,2004; Adelman et al., Pain Med., Vol. 9:175-185 2008; Silberstein etal., Arch Neurol., Vol. 61:490-495, 2004). In an open-label,flexible-dose study, 20% of patients withdrew from topiramate because ofadverse effects (Nelles et al., Headache, Vol. 49:1454-1465, 2009).Thus, migraine sufferers have an urgent medical need for more effectiveand/or tolerable treatment options.

Calcitonin gene-related peptide (CGRP) belongs to the calcitonin familyof peptides, which also includes calcitonin, amylin, and adrenomedullin.CGRP is a 37-amino acid peptide expressed in both the central andperipheral nervous systems, and has been implicated as a key mediator inthe initiation and progression of migraine pain. In addition to itsability to act as a vasodilator, CGRP also acts as a neurotransmitter inthe trigeminal ganglion and the trigeminal nucleus caudalis,facilitating synaptic transmission and pain responses (Durham et al.,Curr Opin Investig Drugs, Vol. 5:731-735, 2004; Zimmermann et al., BrainRes., Vol. 724:238-245, 1996; Wang et al., Proc Natl Acad Sci USA., Vol.92:11480-11484, 1995; Poyner, Pharmacol. Ther., Vol. 56:23-51, 1992).

The CGRP receptor is a complex composed of the G-protein coupledcalcitonin-like receptor (CLR) and a single transmembrane domain proteinreceptor activity modifying protein (RAMP1). The CGRP receptor complexis located at sites that are relevant to migraine including thecerebrovasculature, the trigeminocervical complex in the brainstem, andthe trigeminal ganglion (Zhang et al., J. Neurosci., Vol. 27: 2693-2703,2007; Storer et al., Br J Pharmacol., Vol. 142:1171-1181, 2004; Oliveret al., J Cereb Blood Flow Metab., Vol. 22:620-629, 2002). Several linesof evidence indicate that CGRP is a potent vasodilator and nociceptivemodulator that has been associated with migraine pathophysiology: (1) itis expressed in the trigeminal system, which is implicated in thepathophysiology of migraines; (2) CGRP levels are elevated inmigraineurs during an attack (Bellamy et al., Headache, Vol. 46:24-33,2006; Ashina et al., Pain, Vol. 86:133-138, 2000; Gallai et al.,Cephalalgia, Vol. 15:384-390, 1995; Goadsby et al., Ann Neurol., Vol.28:183-187, 1990; Goadsby et al., Ann Neurol., Vol. 23:193-196, 1988);(3) acute migraine therapies such as triptans restore CGRP levels tonormal after treatment (Juhasz et al., Cephalalgia, Vol. 25:179-183,2005); (4) CGRP infusion triggers the onset of migraine headaches inmigraine sufferers (Petersen et al., Br J Pharmacol., Vol.143:1074-1075, 2004; Lassen et al., Cephalalgia, Vol. 22:54-61, 2002);and (5) CGRP antagonists have demonstrated efficacy in acute migrainereversal (Connor et al., Neurology, Vol. 73:970-977, 2009; Hewitt etal., Abstract for the 14^(th) Congress of the International HeadacheSociety, 2009; LBOR3; Ho et al., Lancet, Vol. 372:2115-2123, 2008a; Hoet al., Neurology, Vol. 70:1304-1312, 2008b). Additionally,small-molecule CGRP receptor antagonists and antibody CGRP ligandantagonists have demonstrated clinical efficacy in episodic migraineprevention (Dodick et al., Lancet Neurol., Vol. 13:1100-1107, 2014a;Dodick et al., Lancet Neurol., Vol. 13:885-892 2014b; Ho et al.,Neurology, Vol. 83:958-966, 2014). Taken together, these data suggest arole for the CGRP neuropeptide and its receptor in the pathogenesis ofmigraine.

Pituitary adenylate cyclase-activating polypeptide (PACAP) belongs tothe VIP/secretin/glucagon superfamily. The sequence of PACAP 27corresponds to the 27 N-terminal amino acids of PACAP 38 and shares 68%identity with vasoactive intestinal polypeptide (VIP) (Pantaloni et al.,J. Biol. Chem., Vol. 271: 22146-22151, 1996; Pisegna and Wank, Proc.Natl. Acad. Sci. USA, Vol. 90: 6345-49, 1993; Campbell and Scanes,Growth Regul., Vol. 2:175-191, 1992). The major form of PACAP peptide inthe human body is PACAP 38 and the pharmacology of PACAP 38 and PACAP 27has not been shown to be different from each other. Three PACAPreceptors have been reported: one receptor that binds PACAP with highaffinity and has a much lower affinity for VIP (PAC1 receptor), and theother two receptors that recognize PACAP and VIP equally well (VPAC1 andVPAC2 receptors) (Vaudry et al., Pharmacol Rev., Vol. 61:283-357, 2009).PACAP is capable of binding all three receptors with similar potency andis thus not particularly selective. VIP, on the other hand, binds withsignificantly higher affinity to VPAC1 and VPAC2, as compared with PAC1.In addition to endogenous agonists PACAP and VIP, maxadilan, a 65 aminoacid peptide originally isolated from the sand-fly, is exquisitelyselective for PAC1 compared with VPAC1 or VPAC2.

Human experimental migraine models using PACAP as a challenge agent toinduce migraine-like headaches support the role of PAC1 receptorantagonism as a potential treatment for migraine prophylaxis. Infusionof PACAP 38 causes headaches in healthy subjects and migraine-likeheadaches in migraine patients (Schytz et al., Brain, Vol. 132:16-25,2009). In addition, in the same model, VIP does not cause migraine-likeheadaches in migraine patients (Rahmann et al., Cephalalgia, Vol.28:226-236, 2008). The lack of migraine-like headache induction from VIPinfusion suggests that PAC1 receptor, but not VPAC1 or VPAC2 receptors,is involved in migraine because VIP has a much higher affinity at thelatter two receptors. These data suggest that a selective PAC1antagonist has the potential to treat migraine.

There is a need in the art to develop migraine-specific prophylactictherapies having novel mechanisms of action that are directed to targetsthat underlie migraine pathophysiology. In particular, therapeuticmolecules having a dual function in antagonizing both the CGRP/CGRPreceptor and PACAP/PAC1 receptor pathways would be particularlybeneficial.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the design and generation ofbispecific antigen binding proteins capable of blocking both the humanCGRP receptor and the human PAC1 receptor. Such bispecific antigenbinding proteins comprise a first binding domain that specifically bindsto human CGRP receptor and a second binding domain that specificallybinds to human PAC1 receptor. In some embodiments, each of the bindingdomains comprises variable regions from immunoglobulin light and heavychains. The binding domains may be prepared from anti-CGRP receptor andanti-PAC1 receptor antibodies.

In certain embodiments, one of the binding domains is a Fab fragment andthe other binding domain is a single-chain variable fragment (scFv). Inother embodiments, both binding domains are Fab fragments. Thebispecific antigen binding proteins may also comprise an immunoglobulinconstant region or Fc region, which, in some embodiments, is derivedfrom a human immunoglobulin IgG1 or IgG2. In certain embodiments, theconstant region comprises one or more amino acid substitutions thatreduce glycosylation and/or effector function of the bispecific antigenbinding protein.

In some embodiments, the bispecific antigen binding proteins aremonovalent for each target. In such embodiments, the bispecific antigenbinding protein can be an antibody where one antigen binding domain orarm binds to the CGRP receptor and the other antigen binding domain orarm binds to the PAC1 receptor. In other embodiments, the bispecificantigen binding proteins are bivalent for each target. In suchembodiments, one binding domain is positioned at the amino terminus ofan immunoglobulin Fc region and the other binding domain is positionedat the carboxyl terminus of the Fc region such that, when dimerized, theantigen binding protein comprises two antigen binding domains that bindto the CGRP receptor and two antigen binding domains that bind to thePAC1 receptor.

In some embodiments, the bispecific antigen binding protein is anantibody, such as a heterodimeric antibody. The heterodimeric antibodymay comprise a first light chain and a first heavy chain from a firstantibody that specifically binds to human CGRP receptor and a secondlight chain and second heavy chain from a second antibody thatspecifically binds to human PAC1 receptor. In certain embodiments, thefirst and second heavy chains comprise one or more charge pair mutationsin the constant region (e.g. CH3 domain) to promote heterodimerformation. In related embodiments, the first light chain and first heavychain (or second light chain and second heavy chain) comprise one ormore charge pair mutations to facilitate correct light-heavy chainpairing. In some such embodiments, the first heavy chain comprises anamino acid substitution introducing a charged amino acid (e.g. glutamicacid) that has the opposite charge of the amino acid introduced into thefirst light chain (e.g. lysine) so that the first light chain and firstheavy chain are attracted to each other. The charged amino acidintroduced into the second light chain (e.g. glutamic acid) wouldpreferably have the same charge as the amino acid introduced into thefirst heavy chain (e.g. glutamic acid), but the opposite charge of theamino acid introduced into the second heavy chain (e.g. lysine) so thatthe second light chain would be attracted to the second heavy chain, butrepelled from the first heavy chain.

In certain embodiments of the invention, the bispecific antigen bindingprotein is comprised of an antibody against a first target (e.g. CGRPreceptor or PAC1 receptor) and a scFv derived from an antibody against asecond target (e.g. PAC1 receptor or CGRP receptor). In this IgG-scFvformat, the bispecific, multivalent antigen binding protein comprises(i) a light chain and a heavy chain from a first antibody and (ii) ascFv comprising a light chain variable region (VL) and a heavy chainvariable region (VH) from a second antibody, wherein the scFv is fusedat its amino terminus to the carboxyl terminus of the heavy chainoptionally through a peptide linker to form a modified heavy chain, andwherein the first or second antibody specifically binds to human CGRPreceptor and the other antibody specifically binds to human PAC1receptor. In some embodiments, the scFv comprises, from N-terminus toC-terminus, a VH region, a peptide linker, and a VL region. In otherembodiments, the scFv comprises, from N-terminus to C-terminus, a VLregion, a peptide linker, and a VH region.

In other embodiments of the invention, the bispecific antigen bindingprotein is comprised of an antibody against a first target (e.g. CGRPreceptor or PAC1 receptor) and a Fab fragment derived from an antibodyagainst a second target (e.g. PAC1 receptor or CGRP receptor). In thisIgG-Fab format, the bispecific, multivalent antigen binding proteincomprises (i) a light chain from a first antibody, (ii) a heavy chainfrom the first antibody, wherein the heavy chain is fused at itscarboxyl terminus optionally through a peptide linker to a firstpolypeptide comprising VL-CL domains or VH-CH1 domains of a secondantibody to form a modified heavy chain, and (iii) a second polypeptidecomprising VH-CH1 domains or VL-CL domains of the second antibody,wherein the first or second antibody specifically binds to human CGRPreceptor and the other antibody specifically binds to human PAC1receptor. In particular embodiments, the first polypeptide, which isfused to the carboxyl terminus of the heavy chain, comprises VL and CLdomains (i.e. a light chain) from the second antibody, and the secondpolypeptide comprises VH and CH1 domains (i.e. a Fd fragment) from thesecond antibody. In other particular embodiments, the first polypeptide,which is fused to the carboxyl terminus of the heavy chain, comprises VHand CH1 domains (i.e. a Fd fragment) from the second antibody, and thesecond polypeptide comprises VL and CL domains (i.e. a light chain) fromthe second antibody. The CL and CH1 domains may be switched in someembodiments between the first and second polypeptide. Thus, in someembodiments, the first polypeptide, which is fused to the carboxylterminus of the heavy chain, comprises VL and CH1 domains from thesecond antibody, and the second polypeptide comprises VH and CL domainsfrom the second antibody. In other embodiments, the first polypeptide,which is fused to the carboxyl terminus of the heavy chain, comprises VHand CL domains from the second antibody, and the second polypeptidecomprises VL and CH1 domains from the second antibody.

The present invention includes one or more nucleic acids encoding any ofthe bispecific antigen binding proteins described herein or componentsthereof, as well as vectors comprising the nucleic acids. Alsoencompassed within the invention is a recombinant host cell, such as aCHO cell, that expresses any of the bispecific antigen binding proteins.

The bispecific antigen binding proteins described herein can be used inthe manufacture of a pharmaceutical composition or medicament for thetreatment of conditions associated with CGRP receptor and/or PAC1receptor, such as headache, migraine, and chronic pain. Thus, thepresent invention also provides a pharmaceutical composition comprisinga bispecific antigen binding protein and a pharmaceutically acceptablediluent, excipient or carrier.

In some embodiments, the present invention provides a method fortreating or preventing headache in a patient in need thereof comprisingadministering to the patient an effective amount of a bispecific antigenbinding protein described herein. In some embodiments, the headache ismigraine headache. The migraine can be episodic migraine or chronicmigraine. In other embodiments, the headache is cluster headache. Inparticular embodiments, the methods provide prophylactic treatment forthese conditions.

In another embodiment, the present invention provides a method fortreating chronic pain in a patient in need thereof comprisingadministering to the patient an effective amount of a bispecific antigenbinding protein described herein. The chronic pain syndromes to betreated according to the methods of the invention can include arthriticpain, such as pain associated with osteoarthritis or rheumatoidarthritis.

The use of the bispecific antigen binding proteins in any of the methodsdisclosed herein or for preparation of medicaments for administrationaccording to any of the methods disclosed herein is specificallycontemplated. For instance, the present invention includes a bispecificantigen binding protein for use in a method for treating or preventing acondition associated with CGRP receptor and/or PAC1 receptor in apatient in need thereof. The condition can include headache (e.g.migraine headache or cluster headache) and chronic pain.

The present invention also includes the use of a bispecific antigenbinding protein in the preparation of a medicament for treating orpreventing a condition associated with CGRP receptor and/or PAC1receptor in a patient in need thereof. The condition can includeheadache (e.g. migraine headache or cluster headache) and chronic pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic representation of three bispecific heteroimmunoglobulin formats used to generate anti-CGRP receptor/PAC1 receptorbispecific antibodies. The Kabat-EU numbering scheme is used to denotethe positions of charge pair mutations within each of the chains. ThisIgG-like bispecific antibody format is a heterotetramer comprising twodifferent light chains and two different heavy chains. HC1 and LC1 referto the heavy chain and light chain, respectively, of one Fab binding armand HC2 and LC2 refers to the heavy chain and light chain, respectively,of the second Fab binding arm. For example, in the schematic, HC1 andLC1 correspond to the anti-CGRP receptor binding arm and HC2 and LC2correspond to the anti-PAC1 binding arm. However, the two binding armscan be switched such that HC1 and LC1 correspond to the anti-PAC1binding arm and HC2 and LC2 correspond to the anti-CGRP receptor bindingarm.

FIG. 2 depicts a schematic representation of an IgG-scFv format used togenerate anti-CGRP receptor/PAC1 receptor bispecific antigen bindingproteins. In this format, a single-chain variable fragment (scFv), whichcomprises variable domains from a second antibody linked together by aglycine-serine linker, is fused to the carboxyl terminus of the heavychain of a first antibody through a peptide linker to produce a modifiedheavy chain. Although the VH-VL orientation of the variable domainswithin the scFv is shown, the variable domains may also be organized ina VL-VH orientation. The complete molecule is a homotetramer comprisingtwo modified heavy chains and two light chains from the first antibody.

FIG. 3 depicts a schematic representation of an IgG-Fab format used togenerate anti-CGRP receptor/PAC1 receptor bispecific antigen bindingproteins. In this format, one polypeptide chain of a Fab fragment from asecond antibody (e.g. the light chain (VL2-CL)) is fused to the carboxylterminus of the heavy chain of a first antibody through a peptide linkerto produce a modified heavy chain. The complete molecule is homohexamercomprising two modified heavy chains, two light chains from the firstantibody, and two polypeptide chains containing the other half of theFab fragment from the second antibody (e.g. the Fd chain (VH2-CH1)).Charge pair mutations (represented by the circles) can be introducedinto the Fab regions of the first antibody (Fab 1) or second antibody(Fab 2) to promote correct heavy chain-light chain pairs. Although thelight chain of the second antibody is shown as the fusion partner forthe heavy chain of the first antibody in the schematic, the Fd region(VH-CH1) of the second antibody can be fused to the carboxyl terminus ofthe heavy chain with the light chain of the second antibody completingthe Fab domain at the carboxyl terminus of the Fc region.

DETAILED DESCRIPTION

The present invention is directed to bispecific antigen binding proteinsthat specifically bind to both the human CGRP receptor and the humanPAC1 receptor. As both CGRP receptor and PAC1 receptor signaling areimplicated in the control of cerebral vascular tone, the bispecificbinding proteins of the invention provide a means to simultaneouslymodulate both signaling cascades to ameliorate conditions associatedwith dysregulation of the cranial vasculature, such as cluster headacheand migraine. Accordingly, in one embodiment, the present inventionprovides a bispecific antigen binding protein comprising a first bindingdomain that specifically binds to human CGRP receptor and a secondbinding domain that specifically binds to human PAC1 receptor.

As used herein, the term “antigen binding protein” refers to a proteinthat specifically binds to one or more target antigens. An antigenbinding protein can include an antibody and functional fragmentsthereof. A “functional antibody fragment” is a portion of an antibodythat lacks at least some of the amino acids present in a full-lengthheavy chain and/or light chain, but which is still capable ofspecifically binding to an antigen. A functional antibody fragmentincludes, but is not limited to, a single-chain variable fragment(scFv), a nanobody (e.g. VH domain of camelid heavy chain antibodies;VHH fragment, see Cortez-Retamozo et al., Cancer Research, Vol.64:2853-57, 2004), a Fab fragment, a Fab′ fragment, a F(ab′)₂ fragment,a Fv fragment, a Fd fragment, and a complementarity determining region(CDR) fragment, and can be derived from any mammalian source, such ashuman, mouse, rat, rabbit, or camelid. Functional antibody fragments maycompete for binding of a target antigen with an intact antibody and thefragments may be produced by the modification of intact antibodies (e.g.enzymatic or chemical cleavage) or synthesized de novo using recombinantDNA technologies or peptide synthesis.

An antigen binding protein can also include a protein comprising one ormore functional antibody fragments incorporated into a singlepolypeptide chain or into multiple polypeptide chains. For instance,antigen binding proteins can include, but are not limited to, a diabody(see, e.g., EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl.Acad. Sci. USA, Vol. 90:6444-6448, 1993); an intrabody; a domainantibody (single VL or VH domain or two or more VH domains joined by apeptide linker; see Ward et al., Nature, Vol. 341:544-546, 1989); amaxibody (2 scFvs fused to Fc region, see Fredericks et al., ProteinEngineering, Design & Selection, Vol. 17:95-106, 2004 and Powers et al.,Journal of Immunological Methods, Vol. 251:123-135, 2001); a triabody; atetrabody; a minibody (scFv fused to CH3 domain; see Olafsen et al.,Protein Eng Des Sel., Vol. 17:315-23, 2004); a peptibody (one or morepeptides attached to an Fc region, see WO 00/24782); a linear antibody(a pair of tandem Fd segments (VH-CH1-VH-CH1) which, together withcomplementary light chain polypeptides, form a pair of antigen bindingregions, see Zapata et al., Protein Eng., Vol. 8:1057-1062, 1995); asmall modular immunopharmaceutical (see U.S. Patent Publication No.20030133939); and immunoglobulin fusion proteins (e.g. IgG-scFv,IgG-Fab, 2scFv-IgG, 4scFv-IgG, VH-IgG, IgG-VH, and Fab-scFv-Fc).

The antigen binding proteins of the present invention are “bispecific”meaning that they are capable of specifically binding to two differentantigens, human CGRP receptor and human PAC1 receptor. As used herein,an antigen binding protein “specifically binds” to a target antigen whenit has a significantly higher binding affinity for, and consequently iscapable of distinguishing, that antigen, compared to its affinity forother unrelated proteins, under similar binding assay conditions.Antigen binding proteins that specifically bind an antigen may have anequilibrium dissociation constant (K_(D))≤1×10⁻⁶ M. The antigen bindingprotein specifically binds antigen with “high affinity” when the K_(D)is ≤1×10⁻⁸ M. In one embodiment, the antigen binding proteins of theinvention bind to human CGRP receptor and/or human PAC1 receptor with aK_(D) of ≤5×10⁻⁷ M. In another embodiment, the antigen binding proteinsof the invention bind to human CGRP receptor and/or human PAC1 receptorwith a K_(D) of ≤1×10⁻⁷ M. In yet another embodiment, the antigenbinding proteins of the invention bind to human CGRP receptor and/orhuman PAC1 receptor with a K_(D) of ≤5×10⁻⁸M. In another embodiment, theantigen binding proteins of the invention bind to human CGRP receptorand/or human PAC1 receptor with a K_(D) of ≤1×10⁻⁸M. In certainembodiments, the antigen binding proteins of the invention bind to humanCGRP receptor and/or human PAC1 receptor with a K_(D) of ≤5×10⁻⁹M. Inother embodiments, the antigen binding proteins of the invention bind tohuman CGRP receptor and/or human PAC1 receptor with a K_(D) of ≤1×10⁻⁹M. In one particular embodiment, the antigen binding proteins of theinvention bind to human CGRP receptor and/or human PAC1 receptor with aK_(D) of ≤5×10⁻¹⁰ M. In another particular embodiment, the antigenbinding proteins of the invention bind to human CGRP receptor and/orhuman PAC1 receptor with a K_(D) of ≤1×10⁻¹⁰ M.

Affinity is determined using a variety of techniques, an example ofwhich is an affinity ELISA assay. In various embodiments, affinity isdetermined by a surface plasmon resonance assay (e.g., BIAcore®-basedassay). Using this methodology, the association rate constant (k_(a) inM⁻¹s⁻¹) and the dissociation rate constant (k_(a) in s¹) can bemeasured. The equilibrium dissociation constant (K_(D) in M) can then becalculated from the ratio of the kinetic rate constants (k_(a)/k_(a)).In some embodiments, affinity is determined by a kinetic method, such asa Kinetic Exclusion Assay (KinExA) as described in Rathanaswami et al.Analytical Biochemistry, Vol. 373:52-60, 2008. Using a KinExA assay, theequilibrium dissociation constant (K_(D) in M) and the association rateconstant (k_(a) in M⁻¹s⁻¹) can be measured. The dissociation rateconstant (k_(a) in s⁻¹) can be calculated from these values(K_(D)×k_(a)). In other embodiments, affinity is determined by anequilibrium/solution method. In certain embodiments, affinity isdetermined by a FACS binding assay. WO 2010/075238 and WO 2014/144632,both of which are hereby incorporated by reference in their entireties,describe suitable affinity assays for determining the affinity of abinding protein for human CGRP receptor and human PAC1 receptor. Incertain embodiments of the invention, the antigen binding proteinspecifically binds to human CGRP receptor and/or human PAC1 receptorexpressed by a mammalian cell (e.g., CHO, HEK 293, Jurkat), with a K_(D)of 20 nM (2.0×10⁻⁸ M) or less, K_(D) of 10 nM (1.0×10⁻⁸ M) or less,K_(D) of 1 nM (1.0×10⁻⁹ M) or less, K_(D) of 500 pM (5.0×10⁻¹⁰ M) orless, K_(D) of 200 pM (2.0×10⁻¹⁰ M) or less, K_(D) of 150 pM (1.50×10⁻¹⁰M) or less, K_(D) of 125 pM (1.25×10⁻¹⁰ M) or less, K_(D) of 105 pM(1.05×10⁻¹⁰ M) or less, K_(D) of 50 pM (5.0×10¹¹ M) or less, or K_(D) of20 pM (2.0×10¹¹ M) or less, as determined by a Kinetic Exclusion Assay,conducted by the method described in Rathanaswami et al. AnalyticalBiochemistry, Vol. 373:52-60, 2008. In some embodiments, the bispecificantigen binding proteins described herein exhibit desirablecharacteristics such as binding avidity as measured by k_(d)(dissociation rate constant) for human CGRP receptor or human PAC1receptor of about 10⁻², 10⁻³, 10⁻⁴, 10⁻⁵, 10⁻⁶, 10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰s⁻¹ or lower (lower values indicating higher binding avidity), and/orbinding affinity as measured by K_(D) (equilibrium dissociationconstant) for human CGRP receptor or human PAC1 of about 10⁻⁹, 10-10,10¹¹, 10⁻¹², 10⁻¹³, 10⁻¹⁴, 10⁻¹⁵, 10⁻¹⁶ M or lower (lower valuesindicating higher binding affinity).

In some embodiments of the invention, the antigen binding proteins aremultivalent. The valency of the binding protein denotes the number ofindividual antigen binding domains within the binding protein. Forexample, the terms “monovalent,” “bivalent,” and “tetravalent” withreference to the antigen binding proteins of the invention refer tobinding proteins with one, two, and four antigen binding domains,respectively. Thus, a multivalent antigen binding protein comprises twoor more antigen binding domains. In some embodiments, the bispecificantigen binding proteins of the invention are bivalent. Thus, suchbispecific, bivalent antigen binding proteins contain two antigenbinding domains: one antigen-binding domain binding to human CGRPreceptor and one antigen-binding domain binding to human PAC1 receptor.In other embodiments, the bispecific antigen binding proteins aremultivalent. For instance, in certain embodiments, the bispecificantigen binding proteins are tetravalent comprising four antigen-bindingdomains: two antigen-binding domains binding to human CGRP receptor andtwo antigen-binding domains binding to human PAC1 receptor.

As used herein, the term “antigen binding domain,” which is usedinterchangeably with “binding domain,” refers to the region of theantigen binding protein that contains the amino acid residues thatinteract with the antigen and confer on the antigen binding protein itsspecificity and affinity for the antigen. In some embodiments, thebinding domain may be derived from the natural ligands of the human CGRPreceptor and the human PAC1 receptor. For example, the binding domainthat specifically binds to human CGRP receptor may be derived from humanα-CGRP and comprise peptide antagonists, such as the CGRP8-37 antagonistpeptide and variants thereof described in Chiba et al., Am. J. Physiol.,Vol. 256: E331-E335, 1989 and Taylor et al., J. Pharmacol. Exp. Ther.,Vol. 319: 749-757, 2006. Similarly, the binding domain that specificallybinds to human PAC1 receptor may be derived from PACAP38 or PACAP27 andmay comprise peptide antagonists such as those described in Bourgault etal., J. Med. Chem., Vol. 52: 3308-3316, 2009 and U.S. Pat. No.6,017,533.

In certain embodiments of the bispecific antigen binding proteins of theinvention, the binding domain may be derived from an antibody orfunctional fragment thereof. For instance, the binding domains of thebispecific antigen binding proteins of the invention may comprise one ormore complementarity determining regions (CDR) from the light and heavychain variable regions of antibodies that specifically bind to humanCGRP receptor or human PAC1 receptor. As used herein, the term “CDR”refers to the complementarity determining region (also termed “minimalrecognition units” or “hypervariable region”) within antibody variablesequences. There are three heavy chain variable region CDRs (CDRH1,CDRH2 and CDRH3) and three light chain variable region CDRs (CDRL1,CDRL2 and CDRL3). The term “CDR region” as used herein refers to a groupof three CDRs that occur in a single variable region (i.e. the threelight chain CDRs or the three heavy chain CDRs). The CDRs in each of thetwo chains typically are aligned by the framework regions to form astructure that binds specifically with a specific epitope or domain onthe target protein (e.g., human CGRP receptor or human PAC1 receptor).From N-terminus to C-terminus, naturally-occurring light and heavy chainvariable regions both typically conform with the following order ofthese elements: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. A numberingsystem has been devised for assigning numbers to amino acids that occupypositions in each of these domains. This numbering system is defined inKabat Sequences of Proteins of Immunological Interest (1987 and 1991,NIH, Bethesda, Md.), or Chothia & Lesk, 1987, J. Mol. Biol. 196:901-917;Chothia et al., 1989, Nature 342:878-883.

Complementarity determining regions (CDRs) and framework regions (FR) ofa given antibody may be identified using this system. In someembodiments, the anti-CGRP receptor binding domain of the bispecificantigen binding proteins of the invention comprise all six CDRs of theheavy and light chain variable regions of an anti-CGRP receptor antibodyand the anti-PAC1 receptor binding domain of the bispecific antigenbinding proteins of the invention comprise all six CDRs of the heavy andlight chain variable regions of an anti-PAC1 receptor antibody.

In some embodiments of the bispecific antigen binding proteins of theinvention, the binding domains (the anti-CGRP receptor binding domain,the anti-PAC1 receptor binding domain or both) comprise a Fab, a Fab′, aF(ab′)₂, a Fv, a single-chain variable fragment (scFv), or a nanobody.In one embodiment, both binding domains are Fab fragments. In anotherembodiment, one binding domain is a Fab fragment and the other bindingdomain is a scFv.

Papain digestion of antibodies produces two identical antigen-bindingfragments, called “Fab” fragments, each with a single antigen-bindingsite, and a residual “Fc” fragment which contains the immunoglobulinconstant region. The Fab fragment contains all of the variable domain,as well as the constant domain of the light chain and the first constantdomain (CH1) of the heavy chain. Thus, a “Fab fragment” is comprised ofone immunoglobulin light chain (light chain variable region (VL) andconstant region (CL)) and the CH1 region and variable region (VH) of oneimmunoglobulin heavy chain. The heavy chain of a Fab molecule cannotform a disulfide bond with another heavy chain molecule. The Fc fragmentdisplays carbohydrates and is responsible for many antibody effectorfunctions (such as binding complement and cell receptors), thatdistinguish one class of antibody from another. The “Fd fragment”comprises the VH and CH1 domains from an immunoglobulin heavy chain. TheFd fragment represents the heavy chain component of the Fab fragment.

A “Fab′ fragment” is a Fab fragment having at the C-terminus of the CH1domain one or more cysteine residues from the antibody hinge region.

A “F(ab′)₂ fragment” is a bivalent fragment including two Fab′ fragmentslinked by a disulfide bridge between the heavy chains at the hingeregion.

The “Fv” fragment is the minimum fragment that contains a completeantigen recognition and binding site from an antibody. This fragmentconsists of a dimer of one immunoglobulin heavy chain variable region(VH) and one immunoglobulin light chain variable region (VL) in tight,non-covalent association. It is in this configuration that the threeCDRs of each variable region interact to define an antigen binding siteon the surface of the VH-VL dimer. A single light chain or heavy chainvariable region (or half of an Fv fragment comprising only three CDRsspecific for an antigen) has the ability to recognize and bind antigen,although at a lower affinity than the entire binding site comprisingboth VH and VL.

A “single-chain variable antibody fragment” or “scFv fragment” comprisesthe VH and VL regions of an antibody, wherein these regions are presentin a single polypeptide chain, and optionally comprising a peptidelinker between the VH and VL regions that enables the Fv to form thedesired structure for antigen binding (see e.g., Bird et al., Science,Vol. 242:423-426, 1988; and Huston et al., Proc. Natl. Acad. Sci. USA,Vol. 85:5879-5883, 1988).

A “nanobody” is the heavy chain variable region of a heavy-chainantibody. Such variable domains are the smallest fully functionalantigen-binding fragment of such heavy-chain antibodies with a molecularmass of only 15 kDa. See Cortez-Retamozo et al., Cancer Research64:2853-57, 2004. Functional heavy-chain antibodies devoid of lightchains are naturally occurring in certain species of animals, such asnurse sharks, wobbegong sharks and Camelidae, such as camels,dromedaries, alpacas and llamas. The antigen-binding site is reduced toa single domain, the VHH domain, in these animals. These antibodies formantigen-binding regions using only heavy chain variable region, i.e.,these functional antibodies are homodimers of heavy chains only havingthe structure H₂L₂ (referred to as “heavy-chain antibodies” or “HCAbs”).Camelized VHH reportedly recombines with IgG2 and IgG3 constant regionsthat contain hinge, CH2, and CH3 domains and lack a CH1 domain.Camelized VHH domains have been found to bind to antigen with highaffinity (Desmyter et al., J. Biol. Chem., Vol. 276:26285-90, 2001) andpossess high stability in solution (Ewert et al., Biochemistry, Vol.41:3628-36, 2002). Methods for generating antibodies having camelizedheavy chains are described in, for example, U.S. Patent Publication Nos.2005/0136049 and 2005/0037421. Alternative scaffolds can be made fromhuman variable-like domains that more closely match the shark V-NARscaffold and may provide a framework for a long penetrating loopstructure.

In particular embodiments of the bispecific antigen binding proteins ofthe invention, the binding domains comprise an immunoglobulin heavychain variable region (VH) and an immunoglobulin light chain variableregion (VL) of an antibody or antibody fragment which specifically bindsto the desired antigen. For instance, the anti-CGRP receptor bindingdomain of the bispecific antigen binding proteins of the inventioncomprises a VH region and VL region from an anti-CGRP receptor antibodyand the anti-PAC1 receptor binding domain comprises a VH region and VLregion from an anti-PAC1 receptor antibody.

The “variable region,” used interchangeably herein with “variabledomain” (variable region of a light chain (VL), variable region of aheavy chain (VH)) refers to the region in each of the light and heavyimmunoglobulin chains which is involved directly in binding the antibodyto the antigen. As discussed above, the regions of variable light andheavy chains have the same general structure and each region comprisesfour framework (FR) regions whose sequences are widely conserved,connected by three CDRs. The framework regions adopt a beta-sheetconformation and the CDRs may form loops connecting the beta-sheetstructure. The CDRs in each chain are held in their three-dimensionalstructure by the framework regions and form, together with the CDRs fromthe other chain, the antigen binding site.

The binding domains that specifically bind to human CGRP receptor orhuman PAC1 receptor can be derived a) from known antibodies to theseantigens or b) from new antibodies or antibody fragments obtained by denovo immunization methods using the antigen proteins or fragmentsthereof, by phage display, or other routine methods. The antibodies fromwhich the binding domains for the bispecific antigen binding proteinsare derived can be monoclonal antibodies, polyclonal antibodies,recombinant antibodies, human antibodies, or humanized antibodies. Incertain embodiments, the antibodies from which the binding domains arederived are monoclonal antibodies. In these and other embodiments, theantibodies are human antibodies or humanized antibodies and can be ofthe IgG1-, IgG2-, IgG3-, or IgG4-type.

The term “monoclonal antibody” (or “mAb”) as used herein refers to anantibody obtained from a population of substantially homogeneousantibodies, i.e., the individual antibodies comprising the populationare identical except for possible naturally occurring mutations that maybe present in minor amounts. Monoclonal antibodies are highly specific,being directed against an individual antigenic site or epitope, incontrast to polyclonal antibody preparations that typically includedifferent antibodies directed against different epitopes. Monoclonalantibodies may be produced using any technique known in the art, e.g.,by immortalizing spleen cells harvested from the transgenic animal aftercompletion of the immunization schedule. The spleen cells can beimmortalized using any technique known in the art, e.g., by fusing themwith myeloma cells to produce hybridomas. Myeloma cells for use inhybridoma-producing fusion procedures preferably arenon-antibody-producing, have high fusion efficiency, and enzymedeficiencies that render them incapable of growing in certain selectivemedia which support the growth of only the desired fused cells(hybridomas).

Examples of suitable cell lines for use in mouse fusions include Sp-20,P3-X63/Ag8, P3-X63-Ag8.653, NS1/1.Ag 4 1, Sp210-Ag14, FO, NSO/U, MPC-11,MPC11-X45-GTG 1.7 and S194/5XXO Bul; examples of cell lines used in ratfusions include R210.RCY3, Y3-Ag 1.2.3, IR983F and 4B210. Other celllines useful for cell fusions are U-266, GM1500-GRG2, LICR-LON-HMy2 andUC729-6.

In some instances, a hybridoma cell line is produced by immunizing ananimal (e.g., a transgenic animal having human immunoglobulin sequences)with a CGRP receptor or PAC1 receptor immunogen; harvesting spleen cellsfrom the immunized animal; fusing the harvested spleen cells to amyeloma cell line, thereby generating hybridoma cells; establishinghybridoma cell lines from the hybridoma cells, and identifying ahybridoma cell line that produces an antibody that binds CGRP receptoror PAC1 receptor.

Monoclonal antibodies secreted by a hybridoma cell line can be purifiedusing any technique known in the art, such as protein A-Sepharose,hydroxylapatite chromatography, gel electrophoresis, dialysis, oraffinity chromatography. Hybridomas or mAbs may be further screened toidentify mAbs with particular properties, such as the ability to bindcells expressing CGRP receptor or PAC1 receptor, ability to block orinterfere with the binding of the CGRP ligand or PACAP ligand to theirrespective receptors, or the ability to functionally block either of thereceptors, e.g., using a cAMP assay, e.g., as described herein.

In some embodiments, the anti-PAC1 receptor and anti-CGRP receptorbinding domains of the bispecific antigen binding proteins of theinvention may be derived from humanized antibodies against the PAC1receptor and CGRP receptor, respectively. A “humanized antibody” refersto an antibody in which regions (e.g. framework regions) have beenmodified to comprise corresponding regions from a human immunoglobulin.Generally, a humanized antibody can be produced from a monoclonalantibody raised initially in a non-human animal. Certain amino acidresidues in this monoclonal antibody, typically from non-antigenrecognizing portions of the antibody, are modified to be homologous tocorresponding residues in a human antibody of corresponding isotype.Humanization can be performed, for example, using various methods bysubstituting at least a portion of a rodent variable region for thecorresponding regions of a human antibody (see, e.g., U.S. Pat. Nos.5,585,089 and 5,693,762; Jones et al., Nature, Vol. 321:522-525, 1986;Riechmann et al., Nature, Vol. 332:323-27, 1988; Verhoeyen et al.,Science, Vol. 239:1534-1536, 1988). The CDRs of light and heavy chainvariable regions of antibodies generated in another species can begrafted to consensus human FRs. To create consensus human FRs, FRs fromseveral human heavy chain or light chain amino acid sequences may bealigned to identify a consensus amino acid sequence.

New antibodies generated against the human CGRP receptor or the humanPAC1 receptor from which binding domains for the bispecific antigenbinding proteins of the invention can be derived can be fully humanantibodies. A “fully human antibody” is an antibody that comprisesvariable and constant regions derived from or indicative of human germline immunoglobulin sequences. One specific means provided forimplementing the production of fully human antibodies is the“humanization” of the mouse humoral immune system. Introduction of humanimmunoglobulin (Ig) loci into mice in which the endogenous Ig genes havebeen inactivated is one means of producing fully human monoclonalantibodies (mAbs) in mouse, an animal that can be immunized with anydesirable antigen. Using fully human antibodies can minimize theimmunogenic and allergic responses that can sometimes be caused byadministering mouse or mouse-derived mAbs to humans as therapeuticagents.

Fully human antibodies can be produced by immunizing transgenic animals(usually mice) that are capable of producing a repertoire of humanantibodies in the absence of endogenous immunoglobulin production.Antigens for this purpose typically have six or more contiguous aminoacids, and optionally are conjugated to a carrier, such as a hapten.See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. USA90:2551-2555; Jakobovits et al., 1993, Nature 362:255-258; andBruggermann et al., 1993, Year in Immunol. 7:33. In one example of sucha method, transgenic animals are produced by incapacitating theendogenous mouse immunoglobulin loci encoding the mouse heavy and lightimmunoglobulin chains therein, and inserting into the mouse genome largefragments of human genome DNA containing loci that encode human heavyand light chain proteins. Partially modified animals, which have lessthan the full complement of human immunoglobulin loci, are thencross-bred to obtain an animal having all of the desired immune systemmodifications. When administered an immunogen, these transgenic animalsproduce antibodies that are immunospecific for the immunogen but havehuman rather than murine amino acid sequences, including the variableregions. For further details of such methods, see, for example,WO96/33735 and WO94/02602. Additional methods relating to transgenicmice for making human antibodies are described in U.S. Pat. Nos.5,545,807; 6,713,610; 6,673,986; 6,162,963; 5,939,598; 5,545,807;6,300,129; 6,255,458; 5,877,397; 5,874,299 and 5,545,806; in PCTpublications WO91/10741, WO90/04036, WO 94/02602, WO 96/30498, WO98/24893 and in EP 546073B1 and EP 546073A1.

The transgenic mice described above, referred to herein as “HuMab” mice,contain a human immunoglobulin gene minilocus that encodes unrearrangedhuman heavy (mu and gamma) and kappa light chain immunoglobulinsequences, together with targeted mutations that inactivate theendogenous mu and kappa chain loci (Lonberg et al., 1994, Nature368:856-859). Accordingly, the mice exhibit reduced expression of mouseIgM or kappa and in response to immunization, and the introduced humanheavy and light chain transgenes undergo class switching and somaticmutation to generate high affinity human IgG kappa monoclonal antibodies(Lonberg et al., supra.; Lonberg and Huszar, 1995, Intern. Rev. Immunol.13: 65-93; Harding and Lonberg, 1995, Ann. N.Y Acad. Sci. 764:536-546).The preparation of HuMab mice is described in detail in Taylor et al.,1992, Nucleic Acids Research 20:6287-6295; Chen et al., 1993,International Immunology 5:647-656; Tuaillon et al., 1994, J. Immunol.152:2912-2920; Lonberg et al., 1994, Nature 368:856-859; Lonberg, 1994,Handbook of Exp. Pharmacology 113:49-101; Taylor et al., 1994,International Immunology 6:579-591; Lonberg and Huszar, 1995, Intern.Rev. Immunol. 13:65-93; Harding and Lonberg, 1995, Ann. N.Y Acad. Sci.764:536-546; Fishwild et al., 1996, Nature Biotechnology 14:845-851; theforegoing references are hereby incorporated by reference in theirentirety for all purposes. See, further U.S. Pat. Nos. 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661,016;5,814,318; 5,874,299; and 5,770,429; as well as U.S. Pat. No. 5,545,807;International Publication Nos. WO 93/1227; WO 92/22646; and WO 92/03918,the disclosures of all of which are hereby incorporated by reference intheir entirety for all purposes. Technologies utilized for producinghuman antibodies in these transgenic mice are disclosed also in WO98/24893, and Mendez et al., 1997, Nature Genetics 15:146-156, which arehereby incorporated by reference. For example, the HCo7 and HCo12transgenic mice strains can be used to generate additional fully humananti-CGRP receptor and anti-PAC1 receptor antibodies.

Human-derived antibodies can also be generated using phage displaytechniques. Phage display is described in e.g., Dower et al., WO91/17271, McCafferty et al., WO 92/01047, and Caton and Koprowski, Proc.Natl. Acad. Sci. USA, 87:6450-6454 (1990), each of which is incorporatedherein by reference in its entirety. The antibodies produced by phagetechnology are usually produced as antigen binding fragments, e.g. Fv orFab fragments, in bacteria and thus lack effector functions. Effectorfunctions can be introduced by one of two strategies: The fragments canbe engineered either into complete antibodies for expression inmammalian cells, or into bispecific antibody fragments with a secondbinding site capable of triggering an effector function, if desired.Typically, the Fd fragment (VH-CH1) and light chain (VL-CL) ofantibodies are separately cloned by PCR and recombined randomly incombinatorial phage display libraries, which can then be selected forbinding to a particular antigen. The antibody fragments are expressed onthe phage surface, and selection of Fv or Fab (and therefore the phagecontaining the DNA encoding the antibody fragment) by antigen binding isaccomplished through several rounds of antigen binding andre-amplification, a procedure termed panning. Antibody fragmentsspecific for the antigen are enriched and finally isolated. Phagedisplay techniques can also be used in an approach for the humanizationof rodent monoclonal antibodies, called “guided selection” (see Jespers,L. S., et al., Bio/Technology 12, 899-903 (1994)). For this, the Fdfragment of the mouse monoclonal antibody can be displayed incombination with a human light chain library, and the resulting hybridFab library may then be selected with antigen. The mouse Fd fragmentthereby provides a template to guide the selection. Subsequently, theselected human light chains are combined with a human Fd fragmentlibrary. Selection of the resulting library yields entirely human Fab.

The bispecific antigen binding proteins of the invention comprise abinding domain that specifically binds to the human PAC1 receptor. Thehuman PAC1 receptor (also referred to herein as “human PAC1,” “hPAC1,”and “hPAC1 receptor”) is a 468 amino acid protein designated as P41586(PACR_HUMAN) in the UniProtKB/Swiss-Prot database and is encoded by theADCYAP1R1 gene. PACAP-27 and PACAP-38 are the principal endogenousagonists of PAC1. The amino acid sequence of the human PAC1 receptor isset forth below:

(SEQ ID NO: 339) MAGVVHVSLA ALLLLPMAPA MHSDCIFKKE QAMCLEKIQRANELMGFNDS SPGCPGMWDN ITCWKPAHVG EMVLVSCPELFRIFNPDQVW ETETIGESDF GDSNSLDLSD MGVVSRNCTEDGWSEPFPHY FDACGFDEYE SETGDQDYYY LSVKALYTVGYSTSLVTLTT AMVILCRFRK LHCTRNFIHM NLFVSFMLRAISVFIKDWIL YAEQDSNHCF ISTVECKAVM VFFHYCVVSNYFWLFIEGLY LFTLLVETFF PERRYFYWYT IIGWGTPTVCVTVWATLRLY FDDTGCWDMN DSTALWWVIK GPVVGSIMVNFVLFIGIIVI LVQKLQSPDM GGNESSIYLR LARSTLLLIPLFGIHYTVFA FSPENVSKRE RLVFELGLGS FQGFVVAVLYCFLNGEVQAE IKRKWRSWKV NRYFAVDFKH RHPSLASSGVNGGTQLSILS KSSSQIRMSG LPADNLAT

In certain embodiments, the anti-PAC1 binding domain of the bispecificantigen binding proteins of the invention comprises the VH region and/orthe VL region or CDR regions from an anti-PAC1 receptor antibody orfunctional fragment thereof. Preferably, the anti-PAC1 receptor antibodyor functional fragment thereof specifically binds to human PAC1 receptorand prevents or reduces binding of the receptor to PACAP-38 and/orPACAP-27. In some embodiments, the anti-PAC1 receptor antibody orfunctional fragment thereof specifically binds to an extracellularregion of the human PAC1 receptor. In one particular embodiment, theanti-PAC1 receptor antibody or functional fragment thereof specificallybinds to the amino-terminal extracellular domain of the PAC1 receptor(i.e. amino acids 21-155 of SEQ ID NO: 339).

In some embodiments, the anti-PAC1 antibody or functional fragmentthereof from which the anti-PAC1 binding domain of the bispecificantigen binding proteins of the invention is derived selectivelyinhibits the human PAC1 receptor relative to the human VPAC1 and humanVPAC2 receptors. An antibody or functional fragment thereof “selectivelyinhibits” a specific receptor relative to other receptors when the IC50of the antibody in an inhibition assay of the specific receptor is atleast 50-fold lower than the IC50 in an inhibition assay of another“reference” receptor, e.g., a hVPAC1 or hVPAC2 receptor. An “IC50” isthe dose/concentration required to achieve 50% inhibition of abiological or biochemical function. With radioactive ligands, IC50 isthe concentration of a competing ligand that displaces 50% of thespecific binding of the radioligand. The IC50 of any particularsubstance or antagonist can be determined by constructing adose-response curve and examining the effect of different concentrationsof the drug or antagonist on reversing agonist activity in a particularfunctional assay. IC50 values can be calculated for a given antagonistor drug by determining the concentration needed to inhibit half of themaximum biological response of the agonist. Thus, the IC50 value for anyanti-PAC1 antibody or functional fragment thereof can be calculated bydetermining the concentration of the antibody or fragment needed toinhibit half of the maximum biological response of the PACAP ligand(PACAP-27 or PACAP-3.8) in activating the human PAC1 receptor in anyfunctional assay, such as the cAMP assay described in the Examples. Anantibody or functional fragment thereof that selectively inhibits aspecific receptor is understood to be a neutralizing antibody orneutralizing fragment with respect to that receptor. Thus, in someembodiments, the anti-PAC1 receptor antibody or functional fragmentthereof from which the anti-PAC1 binding domain of the bispecificantigen binding proteins of the invention is derived is a neutralizingantibody or fragment of the human PAC1 receptor.

The variable regions or CDR regions of any anti-PAC1 receptor antibodyor functional fragment thereof can be used to construct the anti-PAC1binding domain of any of the bispecific antigen binding proteinsdescribed herein. For instance, the anti-PAC1 binding domain of thebispecific antigen binding proteins of the invention may comprise VHand/or VL regions or one or more CDRs from any of the anti-human PAC1receptor antibodies described in WO 2014/144632, which is herebyincorporated by reference in its entirety. In certain embodiments, theanti-PAC1 antibody from which the anti-PAC1 binding domain is derivedcompetes for binding of the human PAC1 receptor with one or more of thehuman anti-PAC1 antibodies described in WO 2014/144632 or one or more ofthe anti-PAC1 antibodies described below. The term “compete” refers tothe ability of an antibody or other antigen binding protein to interferewith the binding of other antibodies or binding fragments to a target(e.g. the human PAC1 receptor or the human CGRP receptor). The extent towhich an antibody or binding fragment is able to interfere with thebinding of another antibody or binding fragment to a target (e.g. thehuman PAC1 receptor or the human CGRP receptor), and therefore whetherit can be said to compete, can be determined using competition bindingassays. Numerous types of competitive binding assays can be used,including for example: solid phase direct or indirect radioimmunoassay(RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwichcompetition assay (see, e.g., Stahli et al., 1983, Methods in Enzymology9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland etal., 1986, J. Immunol. 137:3614-3619); solid phase direct-labeled assay,solid phase direct-labeled sandwich assay (see, e.g., Harlow and Lane,1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solidphase direct label RIA using I-125 label (see, e.g., Morel et al., 1988,Molec. Immunol. 25:7-15); solid phase direct biotin-avidin EIA (see,e.g., Cheung, et al., 1990, Virology 176:546-552); and direct labeledRIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82). Typically,a competitive binding assay involves the use of purified antigen boundto a solid surface or cells bearing the antigen, an unlabeled testantibody or other antigen binding protein, and a labeled referenceantibody or other antigen binding protein. Competitive inhibition ismeasured by determining the amount of label bound to the solid surfaceor cells in the presence of the test antibody or other antigen bindingprotein. Usually the test antibody or other antigen binding protein ispresent in excess. Antibodies or other antigen binding proteinsidentified by competition assay (i.e. competing antibodies and antigenbinding proteins) include antibodies and antigen binding proteinsbinding to the same epitope as the reference antibody or antigen bindingprotein.

Usually, when a competing antibody or other antigen binding protein ispresent in excess, it will inhibit specific binding of a referenceantibody or other antigen binding protein to a target antigen by atleast 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%. In some instances,binding of the reference antibody or other antigen binding protein isinhibited by at least 80%, 85%, 90%, 95%, or 97% or more. In someembodiments, a competing antibody or binding fragment thereof reduceshuman PAC1 receptor binding of a reference antibody between about 40%and 100%, such as about 60% and about 100%, specifically between about70% and 100%, and more specifically between about 80% and 100%.

A particularly suitable quantitative assay for detecting competitivebinding uses a Biacore machine which measures the extent of interactionsusing surface plasmon resonance technology.

An exemplary Biacore-based competitive binding assay involves theimmobilization of a reference antibody to a sensor chip. The targetantigen is then contacted with the sensor chip where the target antigenis captured by the immobilized reference antibody. Test antibodies arethen injected over the captured target antigen. If the injected testantibody recognizes a distinct epitope from that recognized by theimmobilized antibody, then a second binding event is observed and thetest antibody would be considered not to compete for binding to thetarget antigen with the reference antibody. Another suitablequantitative competition binding assay uses a FACS-based approach tomeasure competition between antibodies in terms of their binding to thehuman PAC1 receptor.

Light chain and heavy chain variable regions and associated CDRs ofexemplary human anti-PAC1 receptor antibodies from which the anti-PAC1binding domain of the bispecific antigen binding proteins of theinvention can be derived or constructed are set forth below in Tables 1Aand 1B, respectively.

TABLE 1AExemplary Anti-PAC1 Receptor Light Chain Variable Region Amino AcidSequences Antibody VL ID. Group VL Amino Acid Sequence CDRL1 CDRL2 CDRL301A, 01C, LV-01 DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLN AASSLQS QQSYSPPFT0lD SQSISRYLNWYQQKPGKAPKLLIY (SEQ ID (SEQ ID (SEQ IDAASSLQSGIPSRFSGSGSGTDFTLT NO: 1) NO: 14) NO: 20)INSLQPEDFATYFCQQSYSPPFTFG PGTKVDIKR (SEQ ID NO: 28) 01B LV-02DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLN AASSLQS QQSYSPPFTSQSISRYLNWYQQKPGKAPKLLIY (SEQ ID (SEQ ID (SEQ IDAASSLQSGIPSRFSGSGSGTDFTLT NO: 1) NO: 14) NO: 20)INSLQPEDFATYFCQQSYSPPFTFG EGTKVDIKR (SEQ ID NO: 29) 02A, 02C LV-03DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLN AASSLQS QQSYSPPFTSQSISRYLNWYQQKPGKAPKLLIY (SEQ ID (SEQ ID (SEQ IDAASSLQSGIPSRFSGSGSGTDFTLT NO: 1) NO: 14) NO: 20)INSLQPEDFATYFCQQSYSPPFTFG QGTKVDIKR (SEQ ID NO: 30) 03A, 03C, LV-04DIQLTQSPSFLSASVGDRVTITCRA RASQSIGRSLH YASQSLS HQSSRLPFT 03DSQSIGRSLHWYQQKPGKAPKLLIK (SEQ ID (SEQ ID (SEQ IDYASQSLSGVPSRFSGSGSGTEFTL NO: 2) NO: 15) NO: 21)TISSLQPEDFATYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 31) 03B LV-05DIQLTQSPSFLSASVGDRVTITCRA RASQSIGRSLH YASQSLS HQSSRLPFTSQSIGRSLHWYQQKPGKAPKLLIK (SEQ ID (SEQ ID (SEQ IDYASQSLSGVPSRFSGSGSGTEFTL NO: 2) NO: 15) NO: 21)TISSLQPEDFATYYCHQSSRLPFTF GEGTKVDIKR (SEQ ID NO: 32) 04A, 04C, LV-06EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT 04DSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID (SEQ ID (SEQ ID KYASQSLSGIPARFSGSGSGTDFTNO: 3) NO: 15) NO: 21) LTISSLEPEDFAVYYCHQSSRLPFT FGPGTKVDIKR(SEQ ID NO: 33) 04B LV-07 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLSHQSSRLPFT SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID (SEQ ID (SEQ IDKYASQSLSGIPARFSGSGSGTDFT NO: 3) NO: 15) NO: 21)LTISSLEPEDFAVYYCHQSSRLPFT FGEGTKVDIKR (SEQ ID NO: 34) 05A, 05C, LV-08DIVMTQSPDSLAVSLGERATIHCK KSSQSVLYSSN RASTRES QQYYSAPF 05DSSQSVLYSSNNKNFLTWYQQKPG NKNFLT (SEQ ID T QPPKLLIYRASTRESGVPDRFSGS(SEQ ID NO: 16) (SEQ ID GSGTDFTLTISSLQAEDVAVYFCQ NO: 4) NO: 22)QYYSAPFTFGPGTRVDIKR (SEQ ID NO: 35) 05B LV-09 DIVMTQSPDSLAVSLGERATIHCKKSSQSVLYSSN RASTRES QQYYSAPF SSQSVLYSSNNKNFLTWYQQKPG NKNFLT (SEQ ID TQPPKLLIYRASTRESGVPDRFSGS (SEQ ID NO: 16) (SEQ IDGSGTDFTLTISSLQAEDVAVYFCQ NO: 4) NO: 22) QYYSAPFTFGEGTRVDIKR(SEQ ID NO: 36) 06A, 06C LV-10 DIVMTQSPDSLAVSLGERATINCK KSSQSVLYSSNRASTRES QQYYSAPF SSQSVLYSSNNKNFLTWYQQKPG NKNFLT (SEQ ID TQPPKLLIYRASTRESGVPDRFSGS (SEQ ID NO: 16) (SEQ IDGSGTDFTLTISSLQAEDVAVYFCQ NO: 4) NO: 22) QYYSAPFTFGPGTRVDIKR(SEQ ID NO: 37) 06B LV-11 DIVMTQSPDSLAVSLGERATINCK KSSQSVLYSSN RASTRESQQYYSAPF SSQSVLYSSNNKNFLTWYQQKPG NKNFLT (SEQ ID TQPPKLLIYRASTRESGVPDRFSGS (SEQ ID NO: 16) (SEQ IDGSGTDFTLTISSLQAEDVAVYFCQ NO: 4) NO: 22) QYYSAPFTFGEGTRVDIKR(SEQ ID NO: 38) 07 LV-12 EIVLTQSPDFQSVTPKEKVTITCRA RASQSIGSSLH YASQSLSHQSSRLPFT SQSIGSSLHWYQQKPDQSPKLLIK (SEQ ID (SEQ ID (SEQ IDYASQSLSGIPSRFSGSGSGTHFTLT NO: 5) NO: 15) NO: 21)INSLEAEDAATYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 39) 08, 09, 10 LV-13EIVLTQSPDFQSVTPKEKVTITCRA RASQSVGRSLH YASQSLS HQSSRLPFTSQSVGRSLHWYHQKPDQSPKLLI (SEQ ID (SEQ ID (SEQ ID KYASQSLSGVPSRFSGSGSGTDFTNO: 3) NO: 15) NO: 21) LIINSLEAEDAATYYCHQSSRLPFT FGPGTKVDIKR(SEQ ID NO: 40) 11 LV-14 DIQLTQSPSFLSASVGDRVTITCRA RASQSIGRSLH YASQSLSHQSSRLPFT SQSIGRSLHWYHQKPGKAPKLLIK (SEQ ID (SEQ ID (SEQ IDYASQSLSGVPSRFSGSGSGTEFTLI NO: 2) NO: 15) NO: 21)ISSLQPEDFATYYCHQSSRLPFTFG PGTKVDIKR (SEQ ID NO: 41) 12, 13, 14 LV-15EIVLTQSPDFQSVTPKEKVTITCRA RASQSVGRSLH YASQSLS HQSSRLPFTSQSVGRSLHWYQQKPDQSPKLLI (SEQ ID (SEQ ID (SEQ ID KYASQSLSGVPSRFSGSGSGTDFTNO: 3) NO: 15) NO: 21) LTINSLEAEDAATYYCHQSSRLPF TFGPGTKVDIKR(SEQ ID NO: 42) 15, 16, 17, LV-16 EIVLTQSPGTLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT 18 SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID (SEQ ID (SEQ IDKYASQSLSGIPDRFSGSGSGTDFT NO: 3) NO: 15) NO: 21)LTISRLEPEDFATYYCHQSSRLPFT FGQGTKVEIKR (SEQ ID NO: 43) 19 LV-17EIVLTQSPDFQSVTPKEKVTITCRA RASQSIGRSLH YASQSLS HQSSRLPFTSQSIGRSLHWYQQKPDQSPKLLF (SEQ ID (SEQ ID (SEQ ID KYASQSLSGVPSRFSGSGSGTDFTNO: 2) NO: 15) NO: 21) LTINSLEAEDAATYYCHQSSRLPF TFGPGTKVDIKR(SEQ ID NO: 44) 20 LV-18 DIQLTQSPSFLSASVGDRVTITCRA RASQSIGRSLH YASQSLSHQSSRLPFT SQSIGRSLHWYQQKPGKAPKLLF (SEQ ID (SEQ ID (SEQ IDKYASQSLSGVPSRFSGSGSGIEFT NO: 2) NO: 15) NO: 21)LTISSLQPEDFATYYCHQSSRLPFT FGPGTKVDIKR (SEQ ID NO: 45) 21 LV-19EIVLTQSPGTLSLSPGERATLSCRA RASQSVSSSYL GASSRAT QRYGSSRTSQSVSSSYLAWYQQKPGQAPRLL A (SEQ ID (SEQ ID IYGASSRATGIPDRFSNSGSGTDFT(SEQ ID NO: 17) NO: 23) LTISRLEPEDFAVYYCQRYGSSRT NO: 6) FGQGTKVEIKR(SEQ ID NO: 46) 22 LV-20 DIVMTQSPLSLPVTPGEPASISCRS RSSQSLLHSNG LGSNRASMQTLQTPF SQSLLHSNGYNYLDWYLQKPGQS YNYLD (SEQ ID TPQLLLYLGSNRASGVPDRFSGSGS (SEQ ID NO: 18) (SEQ ID GTDFTLQISRVEAEDVGVYYCMQNO: 7) NO: 24) TLQTPFTFGPGTKVDIKR (SEQ ID NO: 47) 23 LV-21DIVMTQSPLSLPVTPGEPASISCRS RSSQSLLHSNG LGSNRAS MQTLQTPFSQSLLHSNGYNYLDWYLQKPGQS YNYLD (SEQ ID T PQLLLYLGSNRASGVPDRFSGSGS (SEQ IDNO: 18) (SEQ ID GTDFTLKISRVEAEDVGVYYCMQ NO: 7) NO: 24)TLQTPFTFGPGTKVDIKR (SEQ ID NO: 48) 24 LV-22 EIVLTQSPGTLSLSPGERATLSCRARASQTVSRSYL GASSRAT QQFGSSPW SQTVSRSYLAWYQQKPGQAPRLL A (SEQ ID TIYGASSRATGIPDRFSGSGSGTDFT (SEQ ID NO: 17) (SEQ IDLTISRLEPEDFAVFYCQQFGSSPW NO: 8) NO: 25) TFGQGTKVEIKR (SEQ ID NO: 49) 25LV-23 DIVMTQSPDSLAVSLGERATIHCK KSSQNVLYSSN RASTRES QQYYSAPFSSQNVLYSSNNKNFLTWYQQKPG NKNFLT (SEQ ID T QPPKLLIYRASTRESGVPDRFSGS(SEQ ID  NO: 16) (SEQ ID GSGTDFTLTISSLQAEDVAVYFCQ NO: 9) NO: 22)QYYSAPFTFGPGTKVDIKR (SEQ ID NO: 50) 26 LV-24 DIVMTQSPDSLAVSLGERTTIKCKKSSQSVLYRSN WASTRES QQYYISPLT SSQSVLYRSNNNNFLAWYQQKPG NNNFLA (SEQ ID(SEQ ID QPPKLLIYWASTRESGVPDRFSGS (SEQ ID  NO: 19) NO: 26)GSGTDFTLTISSLQAEDVAVYFCQ NO: 10) QYYISPLTFGGGTKVEIKR (SEQ ID NO: 51) 27LV-25 DIVMTQSPDSLAVSLGERATINCK KSSQSVLYSSN RASTRES QQYYSSPFSSQSVLYSSNNKHYLAWYRQKPG NKHYLA (SEQ ID T QPPKLLIYRASTRESGVPDRFSGS(SEQ ID NO: 16) (SEQ ID GSGTDFTLTISSLQPEDVAVYYCQ NO: 11) NO: 27)QYYSSPFTFGPGTKVDIKR (SEQ ID NO: 52) 28 LV-26 DIVMTQSPDSLAVSLGERATIHCKKSSQSVLYSSN RASTRES QQYYSAPF SSQSVLYSSNNRNFLSWYQQKPG NRNFLS (SEQ ID TQPPKLLIYRASTRESGVPDRFSGS (SEQ ID NO: 16) (SEQ IDGSGTDFTLTISSLQAEDVAVYFCQ NO: 12) NO: 22) QYYSAPFTFGPGTTVDIKR(SEQ ID NO: 53) 29 LV-27 DIVMTQSPDSLAVSLGERATINCK KSSQSVLYSSN RASTRESQQYYSSPF SSQSVLYSSNNKNYLAWYRQKPG NKNYLA (SEQ ID TQPPKLLIYRASTRESGVPDRFSGS (SEQ ID NO: 16) (SEQ IDGSGTDFTLTISSLQAEDVAVYHCQ NO: 13) NO: 27) QYYSSPFTFGPGTKVDIKR(SEQ ID NO: 54)

TABLE 1BExemplary Anti-PAC1 Receptor Heavy Chain Variable Region Amino AcidSequences Antibody VH ID. Group VH Amino Acid Sequence CDRH1 CDRH2 CDRH301A, 01C, HV-01 QVQLQQSGPGLVKPSQTLSLTCAI SNSATWN RTYYRSKW GTWKQLW01D, 02A, SGDSVSSNSATWNWIRQSPSRGL (SEQ ID SNHYAVSV FLDH 02CEWLGRTYYRSKWSNHYAVSVKS NO: 55) KS (SEQ ID RITINPDTSKSQFSLQLNSVTPEDT(SEQ ID NO: 74) AVYYCARGTWKQLWFLDHWGQ NO: 66) GTLVTVSS (SEQ ID NO: 83)01B HV-02 QVQLQQSGPGLVKPSQTLSLTCAI SNSATWN RTYYRSKW GTWKQLWSGDSVSSNSATWNWIRQSPSRKL (SEQ ID SNHYAVSV FLDH EWLGRTYYRSKWSNHYAVSVKSNO: 55) KS (SEQ ID RITINPDTSKSQFSLQLNSVTPEDT (SEQ ID NO: 74)AVYYCARGTWKQLWFLDHWGQ NO: 66) GTLVTVSS (SEQ ID NO: 84) 03A, 03C, HV-03QVQLVESGAEVVKPGASVKVSCK RFAMH VISYDGGN GYDVLTGY 03D, 09,ASGFTFSRFAMHWVRQAPGQGLE (SEQ ID KYYAESVK PDY 13, 15WMGVISYDGGNKYYAESVKGRV NO: 56) G (SEQ ID TMTRDTSTSTLYMELSSLRSEDTA(SEQ ID NO: 75) VYYCARGYDVLTGYPDYWGQGT NO: 67) LVTVSS (SEQ ID NO: 85)03B HV-04 QVQLVESGAEVVKPGASVKVSCK RFAMH VISYDGGN GYDVLTGYASGFTFSRFAMHWVRQAPGQKLE (SEQ ID KYYAESVK PDY WMGVISYDGGNKYYAESVKGRVNO: 56) G (SEQ ID TMTRDTSTSTLYMELSSLRSEDTA (SEQ ID NO: 75)VYYCARGYDVLTGYPDYWGQGT NO: 67) LVTVSS (SEQ ID NO: 86) 04A, 04C, HV-05QVQLVESGGGVVQPGRSLRLSCA RFAMH VISYDGGN GYDVLTGY 04DASGFTFSRFAMHWVRQAPGKGLE (SEQ ID KYYAESVK PDY WVAVISYDGGNKYYAESVKGRFNO: 56) G (SEQ ID TISRDNSKNTLYLQMNSLRAEDT (SEQ ID NO: 75)ALFYCARGYDVLTGYPDYWGQG NO: 67) TLVTVSS (SEQ ID NO: 87) 04B HV-06QVQLVESGGGVVQPGRSLRLSCA RFAMH VISYDGGN GYDVLTGY ASGFTFSRFAMHWVRQAPGKKLE(SEQ ID KYYAESVK PDY WVAVISYDGGNKYYAESVKGRF NO: 56) G (SEQ IDTISRDNSKNTLYLQMNSLRAEDT (SEQ ID NO: 75) ALFYCARGYDVLTGYPDYWGQG NO: 67)TLVTVSS (SEQ ID NO: 88) 05A, 05C, HV-07 QVQLQESGPGLVKPSQTLSLTCTV SGGYYWSYIYYSGNT GGAARGM 05D SGGSISSGGYYWSWIRQHPGKGL (SEQ ID YYNPSLKS DVEWIGYIYYSGNTYYNPSLKSRVTI NO: 57) (SEQ ID (SEQ ID SGDTSKNQFSLKLRSVTAADTAVNO: 68) NO: 76) YYCTRGGAARGMDVWGQGTTV TVSS (SEQ ID NO: 89) 05B HV-08QVQLQESGPGLVKPSQTLSLTCTV SGGYYWS YIYYSGNT GGAARGMSGGSISSGGYYWSWIRQHPGKKL (SEQ ID YYNPSLKS DV EWIGYIYYSGNTYYNPSLKSRVTINO: 57) (SEQ ID SEQ ID SGDTSKNQFSLKLRSVTAADTAV NO: 68) (NO: 76)YYCTRGGAARGMDVWGQGTTV TVSS (SEQ ID NO: 90) 06A, 06C HV-09QVQLQESGPGLVKPSETLSLTCTV SGGYYWS YIYYSGNT GGAARGMSGGSISSGGYYWSWIRQPPGKGLE (SEQ ID YYNPSLKS DV WIGYIYYSGNTYYNPSLKSRVTISNO: 57) (SEQ ID (SEQ ID VDTSKNQFSLKLRSVTAADTAVY NO: 68) NO: 76)YCTRGGAARGMDVWGQGTTVT VSS (SEQ ID NO: 91) 06B HV-10QVQLQESGPGLVKPSETLSLTCTV SGGYYWS YIYYSGNT GGAARGMSGGSISSGGYYWSWIRQPPGKKLE (SEQ ID YYNPSLKS DV WIGYIYYSGNTYYNPSLKSRVTISNO: 57) (SEQ ID (SEQ ID VDTSKNQFSLKLRSVTAADTAVY NO: 68) NO: 76)YCTRGGAARGMDVWGQGTTVT VSS (SEQ ID NO: 92) 07 HV-11QVQLVESGGGVVQPGRSLRLSCA YYAIH VISYDGSN GYDLLTGY ASGFTFSYYAIHWVRQAPGKGLE(SEQ ID KYYADSVK PDY WVAVISYDGSNKYYADSVKGRF NO: 58) G (SEQ IDTISRDNSKNTLYLQMNSLRAEDT (SEQ ID NO: 77) AVYYCARGYDLLTGYPDYWGQG NO: 69)TLVTVSS (SEQ ID NO: 93) 11, 14 HV-12 QVQLVESGGGVVQPGRSLRLSCA RFAMHVISYDGGN GYDVLTGY ASGFTFSRFAMHWVRRAPGKGLE (SEQ ID KYYAESVK PDYWVAVISYDGGNKYYAESVKGRF NO: 56) G (SEQ ID TISRDNSKNTLNLLMNSLRAEDT (SEQ IDNO: 75) ALFYCARGYDVLTGYPDYWGQG NO: 67) TLVTVSS (SEQ ID NO: 94) 08, 12HV-13 QVQLVESGGGVVQPGRSLRLSCA RFAMH VISYDGGN GYDVLTGYASGFTFSRFAMHWVRQAPGKGLE (SEQ ID KYYAESVK PDY WVAVISYDGGNKYYAESVKGRFNO: 56) G (SEQ ID TISRDNSKNTLNLLMNSLRAEDT (SEQ ID NO: 75)ALFYCARGYDVLTGYPDYWGQG NO: 67) TLVTVSS (SEQ ID NO: 95) 10 HV-14QVQLVESGGGVVQPGRSLRLSCA RFAMH VISYDGGN GYDVLTGY ASGFTFSRFAMHWVRRAPGKGLE(SEQ ID KYYAESVK PDY WVAVISYDGGNKYYAESVKGRF NO: 56) G (SEQ IDTISRDNSKNTLNLLMDSLRAEDT (SEQ ID NO: 75) ALFYCARGYDVLTGYPDYWGQG NO: 67)TLVTVSS (SEQ ID NO: 96) 16 HV-15 QVQLVQSGAEVKKPGASVKVSC RFAMH VISYDGGNGYDVLTGY KASGFTFSRFAMHWVRQAPGQG (SEQ ID  KYYAESVK PDYLEWMGVISYDGGNKYYAESVKG NO: 56) G (SEQ ID RVTMTRDTSTSTAYMELSSLRSE (SEQ IDNO: 75) DTAVYYCARGYDVLTGYPDYWG NO: 67) QGTLVTVSS (SEQ ID NO: 97) 17HV-16 QVQLVQSGAEVKKPGASVKVSC RFAMH VISYDGGN GYDVLTGYAASGFTFSRFAMHWVRQAPGQG (SEQ ID KYYAESVK PDY LEWMGVISYDGGNKYYAESVKGNO: 56) G (SEQ ID RVTMTRDNSKNTAYMELSSLRSE (SEQ ID NO: 75)DTAVYYCARGYDVLTGYPDYWG NO: 67) QGTLVTVSS (SEQ ID NO: 98) 18 HV-17EVQLLESGGGLVQPGGSLRLSCA RFAMH VISYDGGN GYDVLTGY ASGFTFSRFAMHWVRQAPGKGLE(SEQ ID KYYAESVK PDY WVAVISYDGGNKYYAESVKGRF NO: 56) G (SEQ IDTISRDNSKNTLYLQMNSLRAEDT (SEQ ID NO: 75) AVYYCARGYDVLTGYPDYWGQ NO: 67)GTLVTVSS (SEQ ID NO: 99) 19, 20 HV-18 QVQLVESGGGVVQPGRSLRLSCA RYAMHVISYDGSN GYDILTGY ASGFTFSRYAMHWVRQASGKGL (SEQ ID KYYADSVK PDYEWVAVISYDGSNKYYADSVKGR NO: 59) G (SEQ ID FTISRDNSKNTLYLLMSSLRAEDT(SEQ ID NO: 78) AVFYCARGYDILTGYPDYWGQG NO: 69) TLVTVSS (SEQ ID NO: 100)21 HV-19 QVQLVQSGAEVKKPGASVKVSC SYGIS WINAYNGH ELELRSFYYKASGYTFTSYGISWVRQAPGQGL (SEQ ID TNYAQTFQ FGMDV EWMGWINAYNGHTNYAQTFQGRNO: 60) G (SEQ ID VTMTTDTSTSTAYMELRSLRSDD (SEQ ID NO: 79)TAVYYCARELELRSFYYFGMDV NO: 70) WGQGTTVPVSS (SEQ ID NO: 101) 22 HV-20QVQLVQSGAEVKKSGASLKVSCK RYGVS WITTYNGN RVRYSGGY ASGYIFTRYGVSWVRQAPGQGLE(SEQ ID TNYAQKLQ SFDN WMGWITTYNGNTNYAQKLQGR NO: 61) G (SEQ IDVTMTIDTSTSTAYMELRSLRSDDT (SEQ ID NO: 80) AVYYCARRVRYSGGYSFDNWGQ NO: 71)GTLVTVSS (SEQ ID NO: 102) 23 HV-21 QVQLVQSGAEVKKSGASLKVSCK RYGVSWITTYNGN RVRYSGGY ASGYIFTRYGVSWVRQAPGQGLE (SEQ ID TNYAQKLQ SFDNWMGWITTYNGNTNYAQKLQGR NO: 61) G (SEQ ID VTMTTDTSTSTAYMELRSLRSDD (SEQ IDNO: 80) TAVYYCARRVRYSGGYSFDNWG NO: 71) QGTLVTVSS (SEQ ID NO: 103) 24HV-22 QVQLQESGPGLVKPSETLSLTCTV SYYWS RIYTSGSTN IASRGWYFSGGSISSYYWSWIRQPAGKGLEWI (SEQ ID YNPSLKS DL GRIYTSGSTNYNPSLKSRVTMSIGNO: 62) (SEQ ID (SEQ ID TSKNQFSLKLSSVTAADTAVYYC NO: 72) NO: 81)AIIASRGWYFDLWGRGTLVTVSS (SEQ ID NO: 104) 25, 28 HV-23QVQLQESGPGLVKPSQTLSLTCTV SGGYYWS YIYYSGNT GGAARGMSGGSISSGGYYWSWIRQHPGKGL (SEQ ID YYNPSLKS DV EWIGYIYYSGNTYYNPSLKSRVTINO: 57) (SEQ ID (SEQ ID SGDTSKNQFSLKLRSVTAADTAV NO: 68) NO: 76)YYCARGGAARGMDVWGQGTTV TVSS (SEQ ID NO: 105) 26 HV-24QVQLQQSGPGLVKPSQTLSLTCAI SNSAAWN RTYYRSRW GVFYSKGASGDSVSSNSAAWNWIRQSPSRGL (SEQ ID YNDYAVSV FDI EWLGRTYYRSRWYNDYAVSVKSNO: 63) KS (SEQ ID RITINPDTSKNQFSLQLNSVTPEDT (SEQ ID NO: 82)AVYYCARGVFYSKGAFDIWGQG NO: 73) TMVTVSS (SEQ ID NO: 106) 27 HV-25QVQLQESGPGLVKPSQTLSLTCTV RGGYYWS YIYYSGNT GGAARGMSGGSISRGGYYWSWIRQHPGKGL (SEQ ID YYNPSLKS DV EWIGYIYYSGNTYYNPSLKSRVIISNO: 64) (SEQ ID (SEQ ID GDTSKNQLSLKLRSVTAADTAVY NO: 68) NO: 76)YCARGGAARGMDVWGQGTTVT VSS (SEQ ID NO: 107) 29 HV-26QVQLQESGPGLVKPSQTLSLTCTV SGGFYWS YIYYSGNT GGAARGMSGGSISSGGFYWSWIRQHPGKGLE (SEQ ID YYNPSLKS DV WIGYIYYSGNTYYNPSLKSRVIISNO: 65) (SEQ ID (SEQ ID GDTSKNQFSLKLSSVTAADTAVY NO: 68) NO: 76)YCARGGAARGMDVWGQGTTVT VSS (SEQ ID NO: 108)

The anti-PAC1 receptor binding domain of the bispecific antigen bindingproteins may comprise one or more of the CDRs presented in Table 1A(light chain CDRs; i.e. CDRLs) and Table 1B (heavy chain CDRs, i.e.CDRHs). For instance, in certain embodiments, the anti-PAC1 receptorbinding domain comprises one or more light chain CDRs selected from (i)a CDRL1 selected from SEQ ID NOs: 1 to 13, (ii) a CDRL2 selected fromSEQ ID NOs: 14 to 19, and (iii) a CDRL3 selected from SEQ ID NOs: 20 to27, and (iv) a CDRL of (i), (ii) and (iii) that contains one or more,e.g., one, two, three, four or more amino acid substitutions (e.g.,conservative amino acid substitutions), deletions or insertions of nomore than five, four, three, two, or one amino acids. In these and otherembodiments, the anti-PAC1 receptor binding domain comprises one or moreheavy chain CDRs selected from (i) a CDRH1 selected from SEQ ID NOs: 55to 65, (ii) a CDRH2 selected from SEQ ID NOs: 66 to 73, and (iii) aCDRH3 selected from SEQ ID NOs: 74 to 82, and (iv) a CDRH of (i), (ii)and (iii) that contains one or more, e.g., one, two, three, four or moreamino acid substitutions (e.g., conservative amino acid substitutions),deletions or insertions of no more than five, four, three, two, or oneamino acids amino acids.

In certain embodiments, the anti-PAC1 receptor binding domain maycomprise 1, 2, 3, 4, 5, or 6 variant forms of the CDRs listed in Tables1A and 1B, each having at least 80%, 85%, 90% or 95% sequence identityto a CDR sequence listed in Tables 1A and 1B. In some embodiments, theanti-PAC1 receptor binding domain includes 1, 2, 3, 4, 5, or 6 of theCDRs listed in Tables 1A and 1B, each differing by no more than 1, 2, 3,4 or 5 amino acids from the CDRs listed in these tables.

In particular embodiments, the anti-PAC1 receptor binding domain of thebispecific antigen binding proteins of the invention comprises a lightchain variable region comprising a CDRL1, a CDRL2, and a CDRL3, wherein:(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 1, 14 and20, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequence of SEQID NOs: 2, 15 and 21, respectively; (c) CDRL1, CDRL2, and CDRL3 have thesequence of SEQ ID NOs: 3, 15 and 21, respectively; (d) CDRL1, CDRL2,and CDRL3 have the sequence of SEQ ID NOs: 4, 16 and 22, respectively;(e) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 5, 15 and21, respectively; (f) CDRL1, CDRL2, and CDRL3 have the sequence of SEQID NOs: 6, 17 and 23, respectively; (g) CDRL1, CDRL2, and CDRL3 have thesequence of SEQ ID NOs: 7, 18 and 24, respectively; (h) CDRL1, CDRL2,and CDRL3 have the sequence of SEQ ID NOs: 8, 17 and 25, respectively;(i) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 9, 16 and22, respectively; (j) CDRL1, CDRL2, and CDRL3 have the sequence of SEQID NOs: 10, 19 and 26, respectively; (k) CDRL1, CDRL2, and CDRL3 havethe sequence of SEQ ID NOs: 11, 16 and 27, respectively; (1) CDRL1,CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 12, 16 and 22,respectively; or (m) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ IDNOs: 13, 16 and 27, respectively.

In other particular embodiments, the anti-PAC1 receptor binding domainof the bispecific antigen binding proteins of the invention comprises aheavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3,wherein: (a) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs:55, 66 and 74, respectively; (b) CDRH1, CDRH2, and CDRH3 have thesequence of SEQ ID NOs: 56, 67 and 75, respectively; (c) CDRH1, CDRH2,and CDRH3 have the sequence of SEQ ID NOs: 57, 68 and 76, respectively;(d) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 58, 69 and77, respectively; (e) CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 59, 69 and 78, respectively; (f) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 60, 70 and 79, respectively; (g) CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 61, 71 and 80,respectively; (h) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 62, 72 and 81, respectively; (i) CDRH1, CDRH2, and CDRH3 have thesequence of SEQ ID NOs: 63, 73 and 82, respectively; (j) CDRH1, CDRH2,and CDRH3 have the sequence of SEQ ID NOs: 64, 68 and 76, respectively;or (k) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 65, 68and 76, respectively.

In certain embodiments, the anti-PAC1 receptor binding domain of thebispecific antigen binding proteins of the invention comprises a lightchain variable region comprising a CDRL1, a CDRL2, and a CDRL3 and aheavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3,wherein:

(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 1, 14 and20, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 55, 66 and 74, respectively;

(b) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 2, 15 and21, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 56, 67 and 75, respectively;

(c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 3, 15 and21, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 56, 67 and 75, respectively;

(d) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 4, 16 and22, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 57, 68 and 76, respectively;

(e) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 5, 15 and21, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 58, 69 and 77, respectively;

(f) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 2, 15 and21, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 59, 69 and 78, respectively;

(g) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 6, 17 and23, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 60, 70 and 79, respectively;

(h) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 7, 18 and24, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 61, 71 and 80, respectively;

(i) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 8, 17 and25, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 62, 72 and 81, respectively;

(j) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 9, 16 and22, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 57, 68 and 76, respectively;

(k) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 10, 19 and26, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 63, 73 and 82, respectively;

(l) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 11, 16 and27, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 64, 68 and 76, respectively;

(m) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 12, 16 and22, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 57, 68 and 76, respectively; or

(n) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 13, 16 and27, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 65, 68 and 76, respectively.

In some embodiments, the anti-PAC1 receptor binding domain of thebispecific antigen binding proteins of the invention comprises a lightchain variable region comprising a CDRL1, a CDRL2, and a CDRL3 and aheavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3,wherein:

(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 1, 14 and20, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 55, 66 and 74, respectively;

(b) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 2, 15 and21, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 56, 67 and 75, respectively;

(c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 3, 15 and21, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 56, 67 and 75, respectively; or

(d) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 4, 16 and22, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 57, 68 and 76, respectively.

The anti-PAC1 receptor binding domain of the antigen binding proteins ofthe invention may comprise a light chain variable region selected fromthe group consisting of LV-01, LV-02, LV-03, LV-04, LV-05, LV-06, LV-07,LV-08, LV-09, LV-10, LV-11, LV-12, LV-13, LV-14, LV-15, LV-16, LV-17,LV-18, LV-19, LV-20, LV-21, LV-22, LV-23, LV-24, LV-25, LV-26, andLV-27, as shown in Table 1A, and/or a heavy chain variable regionselected from the group consisting of HV-01, HV-02, HV-03, HV-04, HV-05,HV-06, HV-07, HV-08, HV-09, HV-10, HV-11, HV-12, HV-13, HV-14, HV-15,HV-16, HV-17, HV-18, HV-19, HV-20, HV-21, HV-22, HV-23, HV-24, HV-25,and HV-26 as shown in Table 1B, and functional fragments, derivatives,muteins and variants of these light chain and heavy chain variableregions.

Each of the light chain variable regions listed in Table 1A may becombined with any of the heavy chain variable regions shown in Table 1Bto form an anti-PAC1 receptor binding domain suitable for incorporationinto the bispecific antigen binding proteins of the invention. Examplesof such combinations include, but are not limited to: LV-01 and HV-01;LV-02 and HV-02; LV-03 and HV-01; LV-04 and HV-03; LV-05 and HV-04;LV-06 and HV-05; LV-07 and HV-06; LV-08 and HV-07; LV-09 and HV-08;LV-10 and HV-09; LV-11 and HV-10; LV-12 and HV-11; LV-13 and HV-13;LV-13 and HV-03; LV-13 and HV-14; LV-14 and HV-12; LV-15 and HV-13;LV-15 and HV-03; LV-15 and HV-12; LV-16 and HV-03; LV-16 and HV-15;LV-16 and HV-16; LV-16 and HV-17; LV-17 and HV-18; LV-18 and HV-18;LV-19 and HV-19; LV-20 and HV-20; LV-21 and HV-21; LV-22 and HV-22;LV-23 and HV-23; LV-24 and HV-24; LV-25 and HV-25; LV-26 and HV-23; andLV-27 and HV-26. In certain embodiments, the anti-PAC1 receptor bindingdomain comprises: (a) LV-01 (SEQ ID NO: 28) and HV-01 (SEQ ID NO: 83);(b) LV-03 (SEQ ID NO: 30) and HV-01 (SEQ ID NO: 83); (c) LV-04 (SEQ IDNO: 31) and HV-03 (SEQ ID NO: 85); (d) LV-06 (SEQ ID NO: 33) and HV-05(SEQ ID NO: 87); (e) LV-08 (SEQ ID NO: 35) and HV-07 (SEQ ID NO: 89); or(f) LV-10 (SEQ ID NO: 37) and HV-09 (SEQ ID NO: 91).

In some embodiments, the anti-PAC1 receptor binding domain comprises alight chain variable region comprising a sequence of contiguous aminoacids that differs from the sequence of a light chain variable region inTable 1A, i.e. a VL selected from LV-01, LV-02, LV-03, LV-04, LV-05,LV-06, LV-07, LV-08, LV-09, LV-10, LV-11, LV-12, LV-13, LV-14, LV-15,LV-16, LV-17, LV-18, LV-19, LV-20, LV-21, LV-22, LV-23, LV-24, LV-25,LV-26, and LV-27 at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14or 15 amino acid residues, wherein each such sequence difference isindependently either a deletion, insertion or substitution of one aminoacid, with the deletions, insertions and/or substitutions resulting inno more than 15 amino acid changes relative to the foregoing variabledomain sequences. The light chain variable region in some anti-PAC1binding domains comprises a sequence of amino acids that has at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, at least 97% or at least 99% sequence identity to the amino acidsequences of SEQ ID NOs: 28-54 (i.e. the light chain variable regions inTable 1A).

In these and other embodiments, the anti-PAC1 receptor binding domaincomprises a heavy chain variable region comprising a sequence ofcontiguous amino acids that differs from the sequence of a heavy chainvariable region in Table 1B, i.e., a VH selected from HV-01, HV-02,HV-03, HV-04, HV-05, HV-06, HV-07, HV-08, HV-09, HV-10, HV-11, HV-12,HV-13, HV-14, HV-15, HV-16, HV-17, HV-18, HV-19, HV-20, HV-21, HV-22,HV-23, HV-24, HV-25, and HV-26 at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14 or 15 amino acid residues, wherein each such sequencedifference is independently either a deletion, insertion or substitutionof one amino acid, with the deletions, insertions and/or substitutionsresulting in no more than 15 amino acid changes relative to theforegoing variable domain sequences. The heavy chain variable region insome anti-PAC1 receptor binding domains comprises a sequence of aminoacids that has at least 70%, at least 75%, at least 80%, at least 85%,at least 90%, at least 95%, at least 97% or at least 99% sequenceidentity to the amino acid sequences of SEQ ID NOs: 83-108 (i.e. theheavy chain variable regions in Table 1B).

The term “identity,” as used herein, refers to a relationship betweenthe sequences of two or more polypeptide molecules or two or morenucleic acid molecules, as determined by aligning and comparing thesequences. “Percent identity,” as used herein, means the percent ofidentical residues between the amino acids or nucleotides in thecompared molecules and is calculated based on the size of the smallestof the molecules being compared. For these calculations, gaps inalignments (if any) must be addressed by a particular mathematical modelor computer program (i.e., an “algorithm”). Methods that can be used tocalculate the identity of the aligned nucleic acids or polypeptidesinclude those described in Computational Molecular Biology, (Lesk, A.M., ed.), 1988, New York: Oxford University Press; BiocomputingInformatics and Genome Projects, (Smith, D. W., ed.), 1993, New York:Academic Press; Computer Analysis of Sequence Data, Part I, (Griffin, A.M., and Griffin, H. G., eds.), 1994, New Jersey: Humana Press; vonHeinje, G., 1987, Sequence Analysis in Molecular Biology, New York:Academic Press; Sequence Analysis Primer, (Gribskov, M. and Devereux,J., eds.), 1991, New York: M. Stockton Press; and Carillo et al., 1988,SIAM J. Applied Math. 48:1073. For example, sequence identity can bedetermined by standard methods that are commonly used to compare thesimilarity in position of the amino acids of two polypeptides. Using acomputer program such as BLAST or FASTA, two polypeptide or twopolynucleotide sequences are aligned for optimal matching of theirrespective residues (either along the full length of one or bothsequences, or along a pre-determined portion of one or both sequences).The programs provide a default opening penalty and a default gappenalty, and a scoring matrix such as PAM 250 (a standard scoringmatrix; see Dayhoff et al., in Atlas of Protein Sequence and Structure,vol. 5, supp. 3 (1978)) can be used in conjunction with the computerprogram. For example, the percent identity can then be calculated as:the total number of identical matches multiplied by 100 and then dividedby the sum of the length of the longer sequence within the matched spanand the number of gaps introduced into the longer sequences in order toalign the two sequences. In calculating percent identity, the sequencesbeing compared are aligned in a way that gives the largest match betweenthe sequences.

The GCG program package is a computer program that can be used todetermine percent identity, which package includes GAP (Devereux et al.,1984, Nucl. Acid Res. 12:387; Genetics Computer Group, University ofWisconsin, Madison, Wis.). The computer algorithm GAP is used to alignthe two polypeptides or two polynucleotides for which the percentsequence identity is to be determined. The sequences are aligned foroptimal matching of their respective amino acid or nucleotide (the“matched span”, as determined by the algorithm). A gap opening penalty(which is calculated as 3× the average diagonal, wherein the “averagediagonal” is the average of the diagonal of the comparison matrix beingused; the “diagonal” is the score or number assigned to each perfectamino acid match by the particular comparison matrix) and a gapextension penalty (which is usually 1/10 times the gap opening penalty),as well as a comparison matrix such as PAM 250 or BLOSUM 62 are used inconjunction with the algorithm. In certain embodiments, a standardcomparison matrix (see, Dayhoff et al., 1978, Atlas of Protein Sequenceand Structure 5:345-352 for the PAM 250 comparison matrix; Henikoff etal., 1992, Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919 for the BLOSUM62 comparison matrix) is also used by the algorithm.

Recommended parameters for determining percent identity for polypeptidesor nucleotide sequences using the GAP program include the following:

Algorithm: Needleman et al., 1970, J. Mol. Biol. 48:443-453;

Comparison matrix: BLOSUM 62 from Henikoff et al., 1992, supra;

Gap Penalty: 12 (but with no penalty for end gaps)

Gap Length Penalty: 4

Threshold of Similarity: 0

Certain alignment schemes for aligning two amino acid sequences mayresult in matching of only a short region of the two sequences, and thissmall aligned region may have very high sequence identity even thoughthere is no significant relationship between the two full-lengthsequences. Accordingly, the selected alignment method (GAP program) canbe adjusted if so desired to result in an alignment that spans at least50 contiguous amino acids of the target polypeptide.

The bispecific antigen binding proteins of the invention comprise abinding domain that specifically binds to the human CGRP receptor. Thehuman CGRP receptor (also referred to herein as “CGRPR,” “CGRP R,”“hCGRPR,” and “huCGRPR”) is a heterodimer that comprises the humancalcitonin receptor-like receptor (CRLR) polypeptide (Genbank AccessionNo. U17473.1) and the human receptor activity modifying protein 1(RAMP1) polypeptide (Genbank Accession No. AJ001014). The amino acidsequences for the full-length human CRLR and RAMP1 polypeptides as wellas extracellular domains from both polypeptides are set forth in Table 2below.

TABLE 2 Sequences of human CRLR and human RAMP1 polypeptides PolypeptideSequence Human CRLRMLYSIFHFGLMMEKKCTLYFLVLLPFFMILVTAELEESPEDSIQLGVTRNKIMTAQYECYQKIMQDPIQQAEGVYCNRTWDGWLCWNDVAAGTESMQLCPDYFQDFDPSEKVTKICDQDGNWFRHPASNRTWTNYTQCNVNTHEKVKTALNLFYLTIIGHGLSIASLLISLGIFFYFKSLSCQRITLHKNLFFSFVCNSVVTIIHLTAVANNQALVATNPVSCKVSQFIHLYLMGCNYFWMLCEGIYLHTLIVVAVFAEKQHLMWYYFLGWGFPLIPACIHAIARSLYYNDNCWISSDTHLLYIIHGPICAALLVNLFFLLNIVRVLITKLKVTHQAESNLYMKAVRATLILVPLLGIEFVLIPWRPEGKIAEEVYDYIMHILMHFQGLLVSTIFCFFNGEVQAILRRNWNQYKIQFGNSFSNSEALRSASYTVSTISDGPGYSHDCPSEHLNGKSIHDIENVLLKPENLYN (SEQ ID NO: 340) Human RAMP1MARALCRLPRRGLWLLLAHHLFMTTACQEANYGALLRELCLTQFQVDMEAVGETLWCDWGRTIRSYRELADCTWHMAEKLGCFWPNAEVDRFFLAVHGRYFRSCPISGRAVRDPPGSILYPFIVVPITVTLLVTALVVWQSKRTEGIV (SEQ ID NO: 341) ExtracellularELEESPEDSIQLGVTRNKIMTAQYECYQKIMQDPIQQAEGVYCNRTWDGWLCWNDV Domain ofAAGTESMQLCPDYFQDFDPSEKVTKICDQDGNWFRHPASNRTWTNYTQCNVNTHE HumanKVKTA (SEQ ID NO: 342) CRLR ExtracellularCQEANYGALLRELCLTQFQVDMEAVGETLWCDWGRTIRSYRELADCTWHMAEKL Domain ofGCFWPNAEVDRFFLAVHGRYFRSCPISGRAVRDPPGS Human (SEQ ID NO: 343) RAMP1

In certain embodiments, the anti-CGRP receptor binding domain of thebispecific antigen binding proteins of the invention comprises the VHregion and/or the VL region or CDR regions from an anti-CGRP receptorantibody or functional fragment thereof. Preferably, the anti-CGRPreceptor antibody or functional fragment thereof specifically binds tohuman CGRP receptor and prevents or reduces binding of the receptor toCGRP. In certain embodiments, the anti-CGRP receptor antibody orfunctional fragment thereof specifically binds to residues or sequencesof residues, or regions in both human CRLR and human RAMP1 polypeptides.In one embodiment, the anti-CGRP receptor antibody or functionalfragment thereof specifically binds to an epitope formed from aminoacids in both human CRLR and human RAMP1 polypeptides. As used herein,an “epitope” refers to any determinant capable of being specificallybound by an antibody or functional fragment thereof. An epitope can becontiguous or non-contiguous (e.g., (i) in a single-chain polypeptide,amino acid residues that are not contiguous to one another in thepolypeptide sequence but that within in context of the molecule arebound by the antibody or functional fragment, or (ii) in a multimericprotein, e.g., comprising two or more individual components, amino acidresidues present on two or more of the individual components, but thatwithin the context of the multimeric protein are bound by the antibodyor functional fragment). In some embodiments, the epitope formed fromamino acids in both human CRLR and human RAMP1 polypeptides comprisesone or more cleavage sites for AspN protease, which cleaves peptidesafter aspartic acid residues and some glutamic acid residues at theamino end.

In certain embodiments, the anti-CGRP receptor antibody or functionalfragment thereof from which the anti-CGRP receptor binding domain isderived specifically binds to an extracellular domain of human CRLRpolypeptide comprising the amino acid sequence of SEQ ID NO: 342.Alternatively or additionally, the anti-CGRP receptor antibody orfunctional fragment thereof specifically binds to an extracellulardomain of human RAMP1 polypeptide comprising the amino acid sequence ofSEQ ID NO: 343. In some embodiments, the anti-CGRP receptor antibody orbinding fragment specifically binds to an epitope within the human CRLRpolypeptide comprising at least one sequence selected from SEQ ID NO:344 (DSIQLGVTRNKIMTAQY; corresponding to amino acids 8-24 of SEQ ID NO:342), SEQ ID NO: 345 (DVAAGTESMQLCP; corresponding to amino acids 55-67of SEQ ID NO: 342), SEQ ID NO: 346 (DGNWFRHPASNRTWTNYTQCNVNTH;corresponding to amino acids 86-110 of SEQ ID NO: 342), SEQ ID NO: 347(ECYQKIMQ; corresponding to amino acids 25-32 of SEQ ID NO: 342), or SEQID NO: 348 (DGWLCWN; corresponding to amino acids 48-54 of SEQ ID NO:342). For example, in some embodiments, the anti-CGRP receptor antibodyor functional fragment thereof binds an epitope within a subregion ofhuman CRLR polypeptide of SEQ ID NO: 342, wherein the epitope comprisesSEQ ID NOs: 344-348, optionally in its native three-dimensionalconformation. Alternatively or additionally, the anti-CGRP receptorantibody or functional fragment specifically binds to at least oneepitope within the human RAMP1 polypeptide selected from SEQ ID NO: 349(RELADCTWHMAE; corresponding to amino acids 41-52 of SEQ ID NO: 343),SEQ ID NO: 350 (DWGRTIRSYRELA; corresponding to amino acids 32-44 of SEQID NO: 343), SEQ ID NO: 351 (ELCLTQFQV; corresponding to amino acids12-20 of SEQ ID NO: 343), or SEQ ID NO: 352 (DCTWHMA; corresponding toamino acids 45-51 of SEQ ID NO: 343). In some embodiments, the anti-CGRPreceptor antibody or functional fragment thereof binds to an epitopewithin a subregion of human RAMP1 polypeptide of SEQ ID NO: 343, whereinthe epitope comprises SEQ ID NOs: 349-352, optionally in its nativethree-dimensional conformation.

In some embodiments, the anti-CGRP receptor antibody or functionalfragment thereof from which the anti-CGRP receptor binding domain of thebispecific antigen binding proteins of the invention is derivedselectively inhibits the human CGRP receptor relative to the humanadrenomedullin 1(AM1), human adrenomedullin 2 (AM2), or human amylinreceptors (e.g. human AMY1 receptor). The human AM1 receptor iscomprised of a human CRLR polypeptide and a RAMP2 polypeptide, whereasthe human AM2 receptor is comprised of a human CRLR polypeptide and aRAMP3 polypeptide. Thus, an antibody or other binding protein that bindsonly CRLR (and not RAMP1) would not be expected to selectively inhibitthe CGRP receptor because the CRLR polypeptide is also a component ofthe AM1 and AM2 receptors. The human amylin (AMY) receptors arecomprised of a human calcitonin receptor (CT) polypeptide and one of theRAMP1, RAMP2, or RAMP3 subunits. Specifically, the human AMY1 receptoris composed of the CT polypeptide and the RAMP1 polypeptide, the humanAMY2 receptor is composed of the CT polypeptide and the RAMP2polypeptide, and the human AMY3 receptor is composed of the CTpolypeptide and the RAMP3 polypeptide. Thus, an antibody or otherbinding protein that binds only RAMP1 (and not CRLR) would not beexpected to selectively inhibit the CGRP receptor because the RAMP1polypeptide is also a component of the human AMY1 receptor. As describedabove, the ability of any antibody or functional fragment thereof toselectively inhibit a particular receptor (e.g. human CGRP receptor)relative to a reference receptor (e.g. human AM1, AM2, or AMY1receptors) can be assessed by determining the IC50 value of the antibodyor functional fragment in an inhibition assay for the target andreference receptors. The IC50 value for any anti-CGRP receptor antibodyor functional fragment thereof can be calculated by determining theconcentration of the antibody or fragment needed to inhibit half of themaximum biological response of the CGRP ligand in activating the humanCGRP receptor in any functional assay, such as the cAMP assay describedin the Examples. In some embodiments, the anti-CGRP receptor antibody orfunctional fragment thereof from which the anti-CGRP receptor bindingdomain of the bispecific antigen binding proteins of the invention isderived is a neutralizing antibody or fragment of the human CGRPreceptor.

The variable regions or CDR regions of any anti-CGRP receptor antibodyor functional fragment thereof can be used to construct the anti-CGRPreceptor binding domain of any of the bispecific antigen bindingproteins described herein. For instance, the anti-CGRP receptor bindingdomain of the bispecific antigen binding proteins of the invention maycomprise VH and/or VL regions or one or more CDRs from any of theanti-human CGRP receptor antibodies described in WO 2010/075238, whichis hereby incorporated by reference in its entirety. In someembodiments, the anti-CGRP receptor antibody from which the anti-CGRPreceptor binding domain is derived competes for binding of the humanCGRP receptor with one or more of the human anti-CGRP receptorantibodies described in WO 2010/075238 or one or more of the anti-CGRPreceptor antibodies described below. In some embodiments, a competingantibody or binding fragment thereof reduces human CGRP receptor bindingof a reference antibody between about 40% and 100%, such as about 60%and about 100%, specifically between about 70% and 100%, and morespecifically between about 80% and 100%. A particularly suitablequantitative assay for detecting competitive binding uses a Biacoremachine which measures the extent of interactions using surface plasmonresonance technology. Another suitable quantitative competition bindingassay uses a FACS-based approach to measure competition betweenantibodies in terms of their binding to the human CGRP receptor.

Light chain and heavy chain variable regions and associated CDRs ofexemplary human anti-CGRP receptor antibodies from which the anti-CGRPreceptor binding domain of the bispecific antigen binding proteins ofthe invention can be derived or constructed are set forth below inTables 3A and 3B, respectively.

TABLE 3AExemplary Anti-CGRP Receptor Light Chain Variable Region Amino AcidSequences Antibody VL ID. Group VL Amino Acid Sequence CDRL1 CDRL2 CDRL350A, 50C, LV- QSVLTQPPSASGTPGQRVTISCSG SGSSSNIGSNYV RNNQRPS AAWDDSLS50D, 70 101 SSSNIGSNYVYWYQQLPGAAPKL Y (SEQ ID GWVLIFRNNQRPSGVPDRFSGSKSGTS (SEQ ID NO: 120) (SEQ IDASLAISGLRSEDEADYYCAAWDD NO: 109) NO: 127) SLSGWVFGGGTKLTVLG(SEQ ID NO: 136) 50B LV- QSVLTQPPSASGTPGQRVTISCSG SGSSSNIGSNYV RNNQRPSAAWDDSLS 102 SSSNIGSNYVYWYQQLPGAAPKL Y (SEQ ID GWVLIFRNNQRPSGVPDRFSGSKSGTS (SEQ ID NO: 120) (SEQ IDASLAISGLRSEDEADYYCAAWDD NO: 109) NO: 127) SLSGWVFGKGTKLTVLG(SEQ ID NO: 137) 51A, 51C, LV- QSVLTQSPSASGTPGQRVTISCSG SGSSSNIGSNYVRNNQRPS AAWDDSLS 51D 103 SSSNIGSNYVYWYQQLPGAAPKL Y (SEQ ID GWVLILRNNQRPSGVPDRFSGSKSGTS (SEQ ID NO: 120) (SEQ IDASLTISGLRSEDEADYYCAAWDD NO: 109) NO: 127) SLSGWVFGGGTKLTVLG(SEQ ID NO: 138) 51B LV- QSVLTQSPSASGTPGQRVTISCSG SGSSSNIGSNYV RNNQRPSAAWDDSLS 104 SSSNIGSNYVYWYQQLPGAAPKL Y (SEQ ID GWVLILRNNQRPSGVPDRFSGSKSGTS (SEQ ID NO: 120) (SEQ IDASLTISGLRSEDEADYYCAAWDD NO: 109) NO: 127) SLSGWVFGKGTKLTVLG(SEQ ID NO: 139) 52A, 52C, LV- QSVLTQPPSVSAAPGQKVTISCSG SGSSSNIGNNYDNNKRPS GTWDSRLS 52D, 53A, 105 SSSNIGNNYVSWYQQLPGTAPKL VS (SEQ ID AVV53C LIYDNNKRPSGIPDRFSGSKSGTST (SEQ ID NO: 121) (SEQ IDTLGITGLQTGDEADYYCGTWDSR NO: 110) NO: 128) LSAVVFGGGTKLTVLG(SEQ ID NO: 140) 52B, 53B LV- QSVLTQPPSVSAAPGQKVTISCSG SGSSSNIGNNYDNNKRPS GTWDSRLS 106 SSSNIGNNYVSWYQQLPGTAPKL VS (SEQ ID  AVVLIYDNNKRPSGIPDRFSGSKSGTST (SEQ ID NO: 121) (SEQ IDTLGITGLQTGDEADYYCGTWDSR NO: 110) NO: 128) LSAVVFGKGTKLTVLG(SEQ ID NO: 141) 54A, 54C, LV- QSVLTQPPSVSAAPGQKVTISCSG SGSSSNIGNNYDNNKRPS GTWDSRLS 56A, 56C, 107 SSSNIGNNYVSWYQQLPGTAPKL VS (SEQ ID AVV 71LIYDNNKRPSGIPDRFSGSKSGTS (SEQ ID NO: 121) (SEQ IDATLGITGLQTGDEADYYCGTWDS NO: 110) NO: 128) RLSAVVFGGGTKLTVLG(SEQ ID NO: 142) 54B, 56B LV- QSVLTQPPSVSAAPGQKVTISCSG SGSSSNIGNNYDNNKRPS GTWDSRLS 108 SSSNIGNNYVSWYQQLPGTAPKL VS (SEQ ID AVVLIYDNNKRPSGIPDRFSGSKSGTS (SEQ ID NO: 121) (SEQ IDATLGITGLQTGDEADYYCGTWDS NO: 110) NO: 128) RLSAVVFGKGTKLTVLG(SEQ ID NO: 143) 55A, 55C LV- QSVLTQPPSVSAAPGQKVTISCSG SGSSSNIGNNYDNNKRPS GTWDSRLS 109 SSSNIGNNYVSWYQQLPGTAPKL VS (SEQ ID AVVLIYDNNKRPSGIPDRFSGSKSGTS (SEQ ID NO: 121) (SEQ IDATLAITGLQTGDEADYYCGTWDS NO: 110) NO: 128) RLSAVVFGGGTKLTVLG(SEQ ID NO: 144) 55B LV- QSVLTQPPSVSAAPGQKVTISCSG SGSSSNIGNNY DNNKRPSGTWDSRLS 110 SSSNIGNNYVSWYQQLPGTAPKL VS (SEQ ID AVVLIYDNNKRPSGIPDRFSGSKSGTS (SEQ ID NO: 121) (SEQ IDATLAITGLQTGDEADYYCGTWDS NO: 110) NO: 128) RLSAVVFGKGTKLTVLG(SEQ ID NO: 145) 57A, 57C, LV- EIVLTQSPGTLSLSPGERATLSCRA RASQSVSSGYLGASSRAT QQYGNSLS 57D, 58A, 111 SQSVSSGYLTWYQQKPGQAPRLL T (SEQ ID R 58CIYGASSRATGIPDRFSGSGSGTDFT (SEQ ID NO: 17) (SEQ IDLTISRLEPEDFAVYYCQQYGNSLS NO: 111) NO: 129) RFGQGTKLEIKR (SEQ ID NO: 146)57B, 58B LV- EIVLTQSPGTLSLSPGERATLSCRA RASQSVSSGYL GASSRAT QQYGNSLS 112SQSVSSGYLTWYQQKPGQAPRLL T (SEQ ID R IYGASSRATGIPDRFSGSGSGTDFT (SEQ IDNO: 17) (SEQ ID LTISRLEPEDFAVYYCQQYGNSLS NO: 111) NO: 129) RFGKGTKLEIKR(SEQ ID NO: 147) 59 LV- QSVLTQPPSVSEAPGQKVTISCSG SGSSSNIGNNY DNNKRPSGTWDSRLS 113 SSSNIGNNYVSWYQQLPGTAPKL VS (SEQ ID  AVVLIYDNNKRPSGIPDRFSGSKSGTS (SEQ ID NO: 121) (SEQ IDATLGITGLQTGDEADYYCGTWDS NO: 110) NO: 128) RLSAVVFGGGTKLTVL(SEQ ID NO: 148) 60 LV- QSVLTQPPSASGTPGQRVTISCSG SGSSSNIGSNYV RSNQRPSAAWDDSLS 114 SSSNIGSNYVYWYQQLPGAAPKL Y (SEQ ID GWVLIFRSNQRPSGVPDRFSGSKSGTS (SEQ ID NO: 122) (SEQ IDASLAISGLRSEDEADYYCAAWDD NO: 109) NO: 127) SLSGWVFGGGTKLTVL(SEQ ID NO: 149) 61 LV- DIQMTQSPSSLSASVGDRVTITCR RASQGIRNDLG AASSLQSLQYNIYPW 115 ASQGIRNDLGWFQQKPGKAPKRL (SEQ ID (SEQ ID TIYAASSLQSGVPSRFSGSGSGTEFT NO: 112) NO: 14) (SEQ IDLTISSLQPEDLATYYCLQYNIYPW NO: 130) TFGQGTKVEIK (SEQ ID NO: 150) 62 LV-SSELTQDPTVSVALGQTVKITCQG QGDSLRSFYAS GKNNRPS NSRDSSVY 116DSLRSFYASWYQQKPGQAPVLVF (SEQ ID (SEQ ID HLV YGKNNRPSGIPDRFSGSSSGNTASNO: 113) NO: 123) (SEQ ID LTITGAQAEDEADYYCNSRDSSV NO: 131)YHLVLGGGTKLTVL (SEQ ID NO: 151) 63 LV- DIILAQTPLSLSVTPGQPASISCKSSKSSQSLLHSAG EVSNRFS MQSFPLPLT 117 QSLLHSAGKTYLYWYLQKPGQPP KTYLY (SEQ ID(SEQ ID QLLIYEVSNRFSGVPDRFSGSGSG (SEQ ID NO: 124)  NO: 132)TDFTLKISRVEAEDVGIYYCMQSF NO: 114) PLPLTFGGGTKVEIK (SEQ ID NO: 152) 64LV- DIVMTQSPLSLPVTPGEPASISCRS RSSQSLLHSFG LGSNRAS MQALQTPF 118SQSLLHSFGYNYLDWYLQKPGQS YNYLD (SEQ ID T PQLLIYLGSNRASGVPDRFSGSGS (SEQ IDNO: 18) (SEQ ID GTDFTLKISRVEAEDVGVYYCMQ NO: 115) NO: 133)ALQTPFTFGPGTKVDIK (SEQ ID NO: 153) 65 LV- DIILTQTPLSLSVTPGQPASISCKSSKSSQSLLHSDG EVSNRFS MQSFPLPLT 119 QSLLHSDGKTYLYWYLQKPGQPP KTYLY (SEQ ID(SEQ ID QLLIYEVSNRFSGEPDRFSGSGSG (SEQ ID NO: 124) NO: 132)TDFTLKISRVEAEDVGTYYCMQS NO: 116) FPLPLTFGGGTKVEIK (SEQ ID NO: 154) 66LV- QSVLTQPPSVSAAPGQKVTISCSG SGSSSNIGNNY DNNKRPS GTWDSRLS 120SSSNIGNNYVSWYQQFPGTAPKL VS (SEQ ID AVV LIYDNNKRPSGIPDRFSGSKSGTS (SEQ IDNO: 121) (SEQ ID ATLGITGLQTGDEADYYCGTWDS NO: 110) NO: 128)RLSAVVFGGGTKLTVL (SEQ ID NO: 155) 67 LV- QSVLTQPPSASGTPGQRVTISCSGSGSSSNIGSNTV TNNQRPS AARDESLN 121 SSSNIGSNTVNWYQQLPGTAPKL N (SEQ ID GVVLIYTNNQRPSGVPDRFSGSKSGTS (SEQ ID NO: 125) (SEQ IDASLAISGLQSEDEADFYCAARDES NO: 117) NO: 134) LNGVVFGGGTKLTVL(SEQ ID NO: 156) 68 LV- DITLTQTPLSLSVSPGQPASISCKS KSSQSLLHSDG EVSNRFSMQSFPLPLT 122 SQSLLHSDGRNYLYWYLQKPGQP RNYLY (SEQ ID (SEQ IDPQLLIYEVSNRFSGLPDRFSGSGS (SEQ ID NO: 124) NO: 132)GTDFTLKISRVEAEDVGIYYCMQS NO: 118) FPLPLTFGGGTKVEIK (SEQ ID NO: 157) 69LV- DIQMTQSPSSLSASVGDRVTITCR RASQGIRKDLG GASSLQS LQYNSFPW 123ASQGIRKDLGWYQQKPGKAPKR (SEQ ID (SEQ ID T LIYGASSLQSGVPSRFSGSGSGIEFNO: 119) NO: 126) (SEQ ID TLTISSLQPEDFATYYCLQYNSFP NO: 135) WTFGQGTKVEIK(SEQ ID NO: 158)

TABLE 3BExemplary Anti-CGRP Receptor Heavy Chain Variable Region Amino AcidSequences Antibody VH ID. Group VH Amino Acid Sequence CDRH1 CDRH2 CDRH350A, 50C, HV- EVQLVESGGGLVKPGGSLRLSCA NAWMS RIKSKTDG DRTGYSIS 50D 101ASGFTFGNAWMSWVRQAPGKGL (SEQ ID GTTDYAAP WSSYYYYY EWVGRIKSKTDGGTTDYAAPVKNO: 159) VKG GMDV GRFTISRDDSKNTLYLQMNSLKTE (SEQ ID (SEQ IDDTAVYFCTTDRTGYSISWSSYYY NO: 167) NO: 179) YYGMDVWGQGTTVTVSS(SEQ ID NO: 190) 50B HV- EVQLVESGGGLVKPGGSLRLSCA NAWMS RIKSKTDG DRTGYSIS102 ASGFTFGNAWMSWVRQAPGKEL (SEQ ID GTTDYAAP WSSYYYYYEWVGRIKSKTDGGTTDYAAPVK NO: 159) VKG GMDV GRFTISRDDSKNTLYLQMNSLKTE(SEQ ID (SEQ ID DTAVYFCTTDRTGYSISWSSYYY NO: 167) NO: 179)YYGMDVWGQGTTVTVSS (SEQ ID NO: 191) 51A, 51C, HV- EVQLVESGGGLVKPGGSLRLSCANAWMS RIKSKTDG DRTGYSIS 51D 103 ASGFTFSNAWMSWVRQAPGKGL (SEQ ID GTTDYTAPWSSYYYYY EWVGRIKSKTDGGTTDYTAPVKG NO: 159) VKG GMDVRFTISRDDSKNTLYLQMNSLKAE (SEQ ID (SEQ ID DTAVYYCTTDRTGYSISWSSYYY NO: 168)NO: 179) YYGMDVWGQGTTVTVSS (SEQ ID NO: 192) 51B HV-EVQLVESGGGLVKPGGSLRLSCA NAWMS RIKSKTDG DRTGYSIS 104ASGFTFSNAWMSWVRQAPGKEL (SEQ ID GTTDYTAP WSSYYYYY EWVGRIKSKTDGGTTDYTAPVKGNO: 159) VKG GMDV RFTISRDDSKNTLYLQMNSLKAE (SEQ ID (SEQ IDDTAVYYCTTDRTGYSISWSSYYY NO: 168) NO: 179) YYGMDVWGQGTTVTVSS(SEQ ID NO: 193) 52A, 52C, HV- QVQLVESGGGVVQPGRSLRLSCA SFGMH VISFDGSIKDRLNYYDS 52D, 105 ASGFTFSSFGMHWVRQAPGKGLE (SEQ ID YSVDSVKG SGYYHYKY54A, 54C, WVAVISFDGSIKYSVDSVKGRFTI NO: 160) (SEQ ID YGMAV 55A, 55C,SRDNSKNTLFLQMNSLRAEDTAV NO: 169) (SEQ ID 59, 66 YYCARDRLNYYDSSGYYHYKYYNO: 180) GMAVWGQGTTVTVSS (SEQ ID NO: 194) 52B, 54B, HV-QVQLVESGGGVVQPGRSLRLSCA SFGMH VISFDGSIK DRLNYYDS 55B 106ASGFTFSSFGMHWVRQAPGKELE (SEQ ID YSVDSVKG SGYYHYKYWVAVISFDGSIKYSVDSVKGRFTI NO: 160) (SEQ ID YGMAV SRDNSKNTLFLQMNSLRAEDTAVNO: 169) (SEQ ID YYCARDRLNYYDSSGYYHYKYY NO: 180) GMAVWGQGTTVTVSS(SEQ ID NO: 195) 53A, 53C, HV- QVQLVESGGGVVQPGRSLRLSCA SFGMH VISFDGSIKDRLNYYES 56A, 56C 107 ASGFTFSSFGMHWVRQAPGKGLE (SEQ ID YSVDSVKG SGYYHYKYWVAVISFDGSIKYSVDSVKGRFTI NO: 160) (SEQ ID YGMAV SRDNSKNTLFLQMNSLRAEDTAVNO: 169) (SEQ ID YYCARDRLNYYESSGYYHYKYY NO: 181) GMAVWGQGTTVTVSS(SEQ ID NO: 196) 53B, 56B HV- QVQLVESGGGVVQPGRSLRLSCA SFGMH VISFDGSIKDRLNYYES 108 ASGFTFSSFGMHWVRQAPGKELE (SEQ ID YSVDSVKG SGYYHYKYWVAVISFDGSIKYSVDSVKGRFTI NO: 160) (SEQ ID YGMAV SRDNSKNTLFLQMNSLRAEDTAVNO: 169) (SEQ ID YYCARDRLNYYESSGYYHYKYY NO: 181) GMAVWGQGTTVTVSS(SEQ ID NO: 197) 57A, 57C, HV- QVQLVESGGGVVQPGRSLRLSCA SYGMH VIWYDGSNAGGIAAAG 57D 109 ASGFTFSSYGMHWVRQAPGKGL (SEQ ID KYYADSVK LYYYYGMEWVAVIWYDGSNKYYADSVKGR NO: 161) G DV FIISRDKSKNTLYLQMNSLRAEDT (SEQ ID(SEQ ID AVYYCARAGGIAAAGLYYYYGM NO: 170) NO: 182) DVWGQGTTVTVSS(SEQ ID NO: 198) 57B HV- QVQLVESGGGVVQPGRSLRLSCA SYGMH VIWYDGSN AGGIAAAG110 ASGFTFSSYGMHWVRQAPGKELE (SEQ ID KYYADSVK LYYYYGMWVAVIWYDGSNKYYADSVKGRF NO: 161) G DV IISRDKSKNTLYLQMNSLRAEDTA (SEQ ID(SEQ ID VYYCARAGGIAAAGLYYYYGMD NO: 170) NO: 182) VWGQGTTVTVSS(SEQ ID NO: 199) 58A, 58C HV- QVQLVESGGGVVQPGRSLRLSCA SYGMH VIWYDGSNAGGIAAAG 111 ASGFTFSSYGMHWVRQAPGKGL (SEQ ID KYYAESVK LYYYYGMEWVAVIWYDGSNKYYAESVKGR NO: 161) G DV FIISRDKSKNTLYLQMNSLRAEDT (SEQ ID(SEQ ID AVYYCARAGGIAAAGLYYYYGM NO: 171) NO: 182) DVWGQGTTVTVSS(SEQ ID NO: 200) 58B HV- QVQLVESGGGVVQPGRSLRLSCA SYGMH VIWYDGSN AGGIAAAG112 ASGFTFSSYGMHWVRQAPGKELE (SEQ ID KYYAESVK LYYYYGMWVAVIWYDGSNKYYAESVKGRF NO: 161) G DV IISRDKSKNTLYLQMNSLRAEDTA (SEQ ID(SEQ ID VYYCARAGGIAAAGLYYYYGMD NO: 171) NO: 182) VWGQGTTVTVSS(SEQ ID NO: 201) 60 HV- EVQLVESGGGLVKPGGSLRLSCA NAWMS RIKSTTDGG DRTGYSIS113 ASGFTFSNAWMSWVRQAPGKGL (SEQ ID TTDYAAPV WSSYYYYYEWVGRIKSTTDGGTTDYAAPVKG NO: 159) KG GMDV RFTISRDDSKNTLYLQMNSLKTED(SEQ ID (SEQ ID TAVYYCTTDRTGYSISWSSYYYY NO: 172) NO: 179)YGMDVWGQGTTVTVSS (SEQ ID NO: 202) 61 HV- EVQLLESGGGLVQPGESLRLSCA SYAMSAISGSGGRT DQREVGPY 114 ASGFTFSSYAMSWVRQAPGKGLE (SEQ ID YYADSVKG SSGWYDYYWVSAISGSGGRTYYADSVKGRFT NO: 162) (SEQ ID YGMDV ISRDNSKNTLYLQMNSLRAEDTANO: 173) (SEQ ID VYYCAKDQREVGPYSSGWYDYY NO: 183) YGMDVWGQGTTVTVSS(SEQ ID NO: 203) 62 HV- QVQLVQSGAEVKKPGASVKVSC GYYMH WINPNSGG DQMSIIML115 KASGYTFTGYYMHWVRQAPGQG (SEQ ID TNYAQKFQ RGVFPPYYLEWMGWINPNSGGTNYAQKFQG NO: 163) G YGMDV RVTMTRDTSISTAYMELSRLRSD (SEQ ID(SEQ ID DTAVYFCARDQMSIIMLRGVFPP NO: 174) NO: 184) YYYGMDVWGQGTTVTVSS(SEQ ID NO: 204) 63, 65, 68 HV- QVQLVESGGGVVQPGRSLRLSCA SYGMH VISYDGSHEERKRVTMS 116 ASGFTFSSYGMHWVRQAPGKGL (SEQ ID SYADSVKG TLYYYFYYEWVAVISYDGSHESYADSVKGRF NO: 161) (SEQ ID GMDV TISRDISKNTLYLQMNSLRAEDTANO: 175) (SEQ ID VYFCARERKRVTMSTLYYYFYY NO: 185) GMDVWGQGTTVTVSS(SEQ ID NO: 205) 64 HV- EVQLVESGGGLVKPGRSLRLSCT DYAMS FIRSRAYGG GRGIAARW117 ASGFTFGDYAMSWFRQAPGKGL (SEQ ID TPEYAASV DY EWIGFIRSRAYGGTPEYAASVKGNO: 164) KG (SEQ ID RFTISRDDSKTIAYLQMNSLKTED (SEQ ID NO: 186)TAVYFCARGRGIAARWDYWGQG NO: 176) TLVTVSS (SEQ ID NO: 206) 67 HV-QVQLVQSGAEVKKPGASVKVSC DYYMY WISPNSGG GGYSGYAG 118KASGYTFTDYYMYWVRQAPGQG (SEQ ID TNYAQKFQ LYSHYYGM LEWMGWISPNSGGTNYAQKFQGNO: 165) G DV RVTMTRDTSISTAYMELSRLRSD (SEQ ID (SEQ IDDTAVYYCVRGGYSGYAGLYSHY NO: 177) NO: 187) YGMDVWGQGTTVTVSS(SEQ ID NO: 207) 69 HV- EVQLVESGGGLVKPGGSLRLSCA TYSMN SISSSSSYR EGVSGSSP119 ASGYTFSTYSMNWVRQAPGKGL (SEQ ID YYADSVKG YSISWYDYEWVSSISSSSSYRYYADSVKGRFT NO: 166) (SEQ ID YYGMDV ISRDNAKNSLYLQMSSLRAEDTANO: 178) (SEQ ID VYYCAREGVSGSSPYSISWYDYY NO: 188) YGMDVWGQGTTVTVSS(SEQ ID NO: 208) 70 HV- EVQLVESGGGLVKPGGSLRLSCA NAWMS RIKSKTDG DRTGYSIS120 ASGFTFGNAWMSWVRQAPGKGL (SEQ ID GTTDYAAP WSSYYYYYEWVGRIKSKTDGGTTDYAAPVK NO: 159) VKG GMDV GRFTISRDDSKNTLYLQMNSLKTE(SEQ ID (SEQ ID DTAVYYCTTDRTGYSISWSSYYY NO: 167) NO: 179)YYGMDVWGQGTTVTVSS (SEQ ID NO: 209) 71 HV- QVQLVESGGGVVQPGRSLRLSCA SFGMHVISFDGSIK DRLNYYDS 121 ASGFTFSSFGMHWVRQAPGKGLE (SEQ ID YSVDSVKG SGYYHYKYWVAVISFDGSIKYSVDSVKGRFTI NO: 160) (SEQ ID YGLAV SRDNSKNTLFLQMNSLRAEDTAVNO: 169) (SEQ ID YYCARDRLNYYDSSGYYHYKYY NO: 189) GLAVWGQGTTVTVSS(SEQ ID NO: 210)

The anti-CGRP receptor binding domain of the bispecific antigen bindingproteins may comprise one or more of the CDRs presented in Table 3A(light chain CDRs; i.e. CDRLs) and Table 3B (heavy chain CDRs, i.e.CDRHs). For instance, in certain embodiments, the anti-CGRP receptorbinding domain comprises one or more light chain CDRs selected from (i)a CDRL1 selected from SEQ ID NOs: 109 to 119, (ii) a CDRL2 selected fromSEQ ID NOs: 14, 17, 18, 120 to 126, and (iii) a CDRL3 selected from SEQID NOs: 127 to 135, and (iv) a CDRL of (i), (ii) and (iii) that containsone or more, e.g., one, two, three, four or more amino acidsubstitutions (e.g., conservative amino acid substitutions), deletionsor insertions of no more than five, four, three, two, or one aminoacids. In these and other embodiments, the anti-CGRP receptor bindingdomain comprises one or more heavy chain CDRs selected from (i) a CDRH1selected from SEQ ID NOs: 159 to 166, (ii) a CDRH2 selected from SEQ IDNOs: 167 to 178, and (iii) a CDRH3 selected from SEQ ID NOs: 179 to 189,and (iv) a CDRH of (i), (ii) and (iii) that contains one or more, e.g.,one, two, three, four or more amino acid substitutions (e.g.,conservative amino acid substitutions), deletions or insertions of nomore than five, four, three, two, or one amino acids amino acids.

In certain embodiments, the anti-CGRP receptor binding domain maycomprise 1, 2, 3, 4, 5, or 6 variant forms of the CDRs listed in Tables3A and 3B, each having at least 80%, 85%, 90% or 95% sequence identityto a CDR sequence listed in Tables 3A and 3B. In some embodiments, theanti-CGRP receptor binding domain includes 1, 2, 3, 4, 5, or 6 of theCDRs listed in Tables 3A and 3B, each differing by no more than 1, 2, 3,4 or 5 amino acids from the CDRs listed in these tables.

In particular embodiments, the anti-CGRP receptor binding domain of thebispecific antigen binding proteins of the invention comprises a lightchain variable region comprising a CDRL1, a CDRL2, and a CDRL3, wherein:(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 109, 120and 127, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequence ofSEQ ID NOs: 110, 121 and 128, respectively; (c) CDRL1, CDRL2, and CDRL3have the sequence of SEQ ID NOs: 111, 17 and 129, respectively; (d)CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 109, 122 and127, respectively; (e) CDRL1, CDRL2, and CDRL3 have the sequence of SEQID NOs: 112, 14 and 130, respectively; (f) CDRL1, CDRL2, and CDRL3 havethe sequence of SEQ ID NOs: 113, 123 and 131, respectively; (g) CDRL1,CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 114, 124 and 132,respectively; (h) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ IDNOs: 115, 18 and 133, respectively; (i) CDRL1, CDRL2, and CDRL3 have thesequence of SEQ ID NOs: 116, 124 and 132, respectively; (j) CDRL1,CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 117, 125 and 134,respectively; (k) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ IDNOs: 118, 124 and 132, respectively; or (1) CDRL1, CDRL2, and CDRL3 havethe sequence of SEQ ID NOs: 119, 126 and 135, respectively.

In other particular embodiments, the anti-CGRP receptor binding domainof the bispecific antigen binding proteins of the invention comprises aheavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3,wherein: (a) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs:159, 167 and 179, respectively; (b) CDRH1, CDRH2, and CDRH3 have thesequence of SEQ ID NOs: 159, 168 and 179, respectively; (c) CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 160, 169 and 180,respectively; (d) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 160, 169 and 181, respectively; (e) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 161, 170 and 182, respectively; (f) CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 161, 171 and 182,respectively; (g) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 159, 172 and 179, respectively; (h) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 162, 173 and 183, respectively; (i) CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 163, 174 and 184,respectively; (j) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 161, 175 and 185, respectively; (k) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 164, 176 and 186, respectively; (1) CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 165, 177 and 187,respectively; (m) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 166, 178 and 188, respectively; or (n) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 160, 169 and 189, respectively.

In certain embodiments, the anti-CGRP receptor binding domain of thebispecific antigen binding proteins of the invention comprises a lightchain variable region comprising a CDRL1, a CDRL2, and a CDRL3 and aheavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3,wherein:

(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 109, 120and 127, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 159, 167 and 179, respectively;

(b) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 109, 120and 127, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 159, 168 and 179, respectively;

(c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 110, 121and 128, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 160, 169 and 180, respectively;

(d) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 110, 121and 128, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 160, 169 and 181, respectively;

(e) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 111, 17 and129, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 161, 170 and 182, respectively;

(f) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 111, 17 and129, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 161, 171 and 182, respectively;

(g) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 109, 122and 127, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 159, 172 and 179, respectively;

(h) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 112, 14 and130, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 162, 173 and 183, respectively;

(i) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 113, 123and 131, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 163, 174 and 184, respectively;

(j) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 114, 124and 132, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 161, 175 and 185, respectively;

(k) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 115, 18 and133, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 164, 176 and 186, respectively;

(l) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 116, 124and 132, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 161, 175 and 185, respectively;

(m) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 117, 125and 134, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 165, 177 and 187, respectively;

(n) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 118, 124and 132, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 161, 175 and 185, respectively;

(o) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 119, 126and 135, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 166, 178 and 188, respectively; or

(p) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 110, 121and 128, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 160, 169 and 189, respectively.

In some embodiments, the anti-CGRP receptor binding domain of thebispecific antigen binding proteins of the invention comprises a lightchain variable region comprising a CDRL1, a CDRL2, and a CDRL3 and aheavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3,wherein:

(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 109, 120and 127, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 159, 167 and 179, respectively;

(b) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 109, 120and 127, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 159, 168 and 179, respectively;

(c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 110, 121and 128, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 160, 169 and 180, respectively;

(d) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 110, 121and 128, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 160, 169 and 181, respectively;

(e) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 111, 17 and129, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 161, 170 and 182, respectively; or

(f) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 111, 17 and129, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 161, 171 and 182, respectively.

The anti-CGRP receptor binding domain of the antigen binding proteins ofthe invention may comprise a light chain variable region selected fromthe group consisting of LV-101, LV-102, LV-103, LV-104, LV-105, LV-106,LV-107, LV-108, LV-109, LV-110, LV-111, LV-112, LV-113, LV-114, LV-115,LV-116, LV-117, LV-118, LV-119, LV-120, LV-121, LV-122, and LV-123, asshown in Table 3A, and/or a heavy chain variable region selected fromthe group consisting of HV-101, HV-102, HV-103, HV-104, HV-105, HV-106,HV-107, HV-108, HV-109, HV-110, HV-111, HV-112, HV-113, HV-114, HV-115,HV-116, HV-117, HV-118, HV-119, HV-120, and HV-121, as shown in Table3B, and functional fragments, derivatives, muteins and variants of theselight chain and heavy chain variable regions.

Each of the light chain variable regions listed in Table 3A may becombined with any of the heavy chain variable regions shown in Table 3Bto form an anti-CGRP receptor binding domain suitable for incorporationinto the bispecific antigen binding proteins of the invention. Examplesof such combinations include, but are not limited to: LV-101 and HV-101;LV-102 and HV-102; LV-103 and HV-103; LV-104 and HV-104; LV-105 andHV-105; LV-106 and HV-106; LV-105 and HV-107; LV-106 and HV-108; LV-107and HV-105; LV-108 and HV-106; LV-109 and HV-105; LV-110 and HV-106;LV-107 and HV-107; LV-108 and HV-108; LV-111 and HV-109; LV-112 andHV-110; LV-111 and HV-111; LV-112 and HV-112; LV-113 and HV-105; LV-114and HV-113; LV-115 and HV-114; LV-116 and HV-115; LV-117 and HV-116;LV-118 and HV-117; LV-119 and HV-116; LV-120 and HV-105; LV-121 andHV-118; LV-122 and HV-116; LV-123 and HV-119; LV-101 and HV-120; andLV-107 and HV-121. In certain embodiments, the anti-CGRP receptorbinding domain comprises: (a) LV-101 (SEQ ID NO: 136) and HV-101 (SEQ IDNO: 190); (b) LV-103 (SEQ ID NO: 138) and HV-103 (SEQ ID NO: 192); (c)LV-105 (SEQ ID NO: 140) and HV-105 (SEQ ID NO: 194); (d) LV-105 (SEQ IDNO: 140) and HV-107 (SEQ ID NO: 196); (e) LV-107 (SEQ ID NO: 142) andHV-105 (SEQ ID NO: 194); (f) LV-109 (SEQ ID NO: 144) and HV-105 (SEQ IDNO: 194); (g) LV-107 (SEQ ID NO: 142) and HV-107 (SEQ ID NO: 196); (h)LV-111 (SEQ ID NO: 146) and HV-109 (SEQ ID NO: 198); or (i) LV-111 (SEQID NO: 146) and HV-111 (SEQ ID NO: 200).

In some embodiments, the anti-CGRP receptor binding domain comprises alight chain variable region comprising a sequence of contiguous aminoacids that differs from the sequence of a light chain variable region inTable 3A, i.e. a VL selected from LV-101, LV-102, LV-103, LV-104,LV-105, LV-106, LV-107, LV-108, LV-109, LV-110, LV-111, LV-112, LV-113,LV-114, LV-115, LV-116, LV-117, LV-118, LV-119, LV-120, LV-121, LV-122,and LV-123 at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15amino acid residues, wherein each such sequence difference isindependently either a deletion, insertion or substitution of one aminoacid, with the deletions, insertions and/or substitutions resulting inno more than 15 amino acid changes relative to the foregoing variabledomain sequences. The light chain variable region in some anti-CGRPbinding domains comprises a sequence of amino acids that has at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, at least 97% or at least 99% sequence identity to the amino acidsequences of SEQ ID NOs: 136-158 (i.e. the light chain variable regionsin Table 3A).

In these and other embodiments, the anti-CGRP receptor binding domaincomprises a heavy chain variable region comprising a sequence ofcontiguous amino acids that differs from the sequence of a heavy chainvariable region in Table 3B, i.e., a VH selected from HV-101, HV-102,HV-103, HV-104, HV-105, HV-106, HV-107, HV-108, HV-109, HV-110, HV-111,HV-112, HV-113, HV-114, HV-115, HV-116, HV-117, HV-118, HV-119, HV-120,and HV-121 at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15amino acid residues, wherein each such sequence difference isindependently either a deletion, insertion or substitution of one aminoacid, with the deletions, insertions and/or substitutions resulting inno more than 15 amino acid changes relative to the foregoing variabledomain sequences. The heavy chain variable region in some anti-CGRPreceptor binding domains comprises a sequence of amino acids that has atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, at least 97% or at least 99% sequence identity to the aminoacid sequences of SEQ ID NOs: 190-210 (i.e. the heavy chain variableregions in Table 3B).

In certain embodiments, the bispecific antigen binding proteins of theinvention are antibodies. As used herein, the term “antibody” refers toa tetrameric immunoglobulin protein comprising two light chainpolypeptides (about 25 kDa each) and two heavy chain polypeptides (about50-70 kDa each). The term “light chain” or “immunoglobulin light chain”refers to a polypeptide comprising, from amino terminus to carboxylterminus, a single immunoglobulin light chain variable region (VL) and asingle immunoglobulin light chain constant domain (CL). Theimmunoglobulin light chain constant domain (CL) can be kappa (κ) orlambda (λ). The term “heavy chain” or “immunoglobulin heavy chain”refers to a polypeptide comprising, from amino terminus to carboxylterminus, a single immunoglobulin heavy chain variable region (VH), animmunoglobulin heavy chain constant domain 1 (CH1), an immunoglobulinhinge region, an immunoglobulin heavy chain constant domain 2 (CH2), animmunoglobulin heavy chain constant domain 3 (CH3), and optionally animmunoglobulin heavy chain constant domain 4 (CH4). Heavy chains areclassified as mu (μ), delta (Δ), gamma (γ), alpha (α), and epsilon (ε),and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE,respectively. The IgG-class and IgA-class antibodies are further dividedinto subclasses, namely, IgG1, IgG2, IgG3, and IgG4, and IgA1 and IgA2,respectively. The heavy chains in IgG, IgA, and IgD antibodies havethree domains (CH1, CH2, and CH3), whereas the heavy chains in IgM andIgE antibodies have four domains (CH1, CH2, CH3, and CH4). Theimmunoglobulin heavy chain constant domains can be from anyimmunoglobulin isotype, including subtypes. The antibody chains arelinked together via inter-polypeptide disulfide bonds between the CLdomain and the CH1 domain (i.e. between the light and heavy chain) andbetween the hinge regions of the antibody heavy chains.

In particular embodiments, the bispecific antigen binding proteins ofthe invention are heterodimeric antibodies (used interchangeably hereinwith “hetero immunoglobulins” or “hetero Igs”), which refer toantibodies comprising two different light chains and two different heavychains. For instance, in some embodiments, the heterodimeric antibodycomprises a light chain and heavy chain from an anti-PAC1 receptorantibody and a light chain and heavy chain from an anti-CGRP receptorantibody. See FIG. 1.

The heterodimeric antibodies can comprise any immunoglobulin constantregion. The term “constant region” as used herein refers to all domainsof an antibody other than the variable region. The constant region isnot involved directly in binding of an antigen, but exhibits variouseffector functions. As described above, antibodies are divided intoparticular isotypes (IgA, IgD, IgE, IgG, and IgM) and subtypes (IgG1,IgG2, IgG3, IgG4, IgA1 IgA2) depending on the amino acid sequence of theconstant region of their heavy chains. The light chain constant regioncan be, for example, a kappa- or lambda-type light chain constantregion, e.g., a human kappa- or lambda-type light chain constant region,which are found in all five antibody isotypes. Examples of humanimmunoglobulin light chain constant region sequences are shown in thefollowing table.

TABLE 4 Exemplary Human Immunoglobulin Light Chain Constant Regions SEQID Designation NO: CL Domain Amino Acid Sequence CL-1 353GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPFEC S CL-2 354GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS CL-3 355GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS CL-7 356GQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPAEC S

The heavy chain constant region of the heterodimeric antibodies can be,for example, an alpha-, delta-, epsilon-, gamma-, or mu-type heavy chainconstant region, e.g., a human alpha-, delta-, epsilon-, gamma-, ormu-type heavy chain constant region. In some embodiments, theheterodimeric antibodies comprise a heavy chain constant region from anIgG1, IgG2, IgG3, or IgG4 immunoglobulin. In one embodiment, theheterodimeric antibody comprises a heavy chain constant region from ahuman IgG1 immunoglobulin. In another embodiment, the heterodimericantibody comprises a heavy chain constant region from a human IgG2immunoglobulin.

Examples of human IgG1 and IgG2 heavy chain constant region sequencesare shown below in Table 5.

TABLE 5 Exemplary Human Immunoglobulin Heavy Chain Constant Regions SEQIg ID isotype NO: Heavy Chain Constant Region Amino Acid Sequence Human357 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV IgG1zLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human 358ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV IgG1zaLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human 359ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV IgG1fLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human 360ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV IgG1faLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human 361ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV IgG2LQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Each of the variable regions disclosed in Tables 1A, 1B, 3A, and 3B maybe attached to the above light and heavy chain constant regions to formcomplete antibody light and heavy chains, respectively. Further, each ofthe so generated heavy and light chain polypeptides may be combined toform a complete bispecific antibody structure, e.g. a heterodimericantibody. It should be understood that the heavy chain and light chainvariable regions provided herein can also be attached to other constantdomains having different sequences than the exemplary sequences listedabove.

To facilitate assembly of the light and heavy chains from the anti-PAC1receptor antibody and the light and heavy chains from the anti-CGRPreceptor antibody into a bispecific, heterodimeric antibody, the lightchains and/or heavy chains from each antibody can be engineered toreduce the formation of mispaired molecules. For example, one approachto promote heterodimer formation over homodimer formation is theso-called “knobs-into-holes” method, which involves introducingmutations into the CH3 domains of two different antibody heavy chains atthe contact interface. Specifically, one or more bulky amino acids inone heavy chain are replaced with amino acids having short side chains(e.g. alanine or threonine) to create a “hole,” whereas one or moreamino acids with large side chains (e.g. tyrosine or tryptophan) areintroduced into the other heavy chain to create a “knob.” When themodified heavy chains are co-expressed, a greater percentage ofheterodimers (knob-hole) are formed as compared to homodimers (hole-holeor knob-knob). The “knobs-into-holes” methodology is described in detailin WO 96/027011; Ridgway et al., Protein Eng., Vol. 9: 617-621, 1996;and Merchant et al., Nat, Biotechnol., Vol. 16: 677-681, 1998, all ofwhich are hereby incorporated by reference in their entireties.

Another approach for promoting heterodimer formation to the exclusion ofhomodimer formation entails utilizing an electrostatic steeringmechanism (see Gunasekaran et al., J. Biol. Chem., Vol. 285:19637-19646, 2010, which is hereby incorporated by reference in itsentirety). This approach involves introducing or exploiting chargedresidues in the CH3 domain in each heavy chain so that the two differentheavy chains associate through opposite charges that cause electrostaticattraction. Homodimerization of the identical heavy chains aredisfavored because the identical heavy chains have the same charge andtherefore are repelled. This same electrostatic steering technique canbe used to prevent mispairing of light chains with the non-cognate heavychains by introducing residues having opposite charges in the correctlight chain-heavy chain pair at the binding interface. The electrostaticsteering technique and suitable charge pair mutations for promotingheterodimers and correct light chain/heavy chain pairing is described inWO2009089004 and WO2014081955, both of which are hereby incorporated byreference in their entireties.

In embodiments in which the bispecific antigen binding proteins of theinvention are heterodimeric antibodies comprising a first light chain(LC1) and first heavy chain (HC1) from a first antibody thatspecifically binds to human CGRP receptor and a second light chain (LC2)and second heavy chain (HC2) from a second antibody that specificallybinds to human PAC1 receptor, HC1 or HC2 may comprise one or more aminoacid substitutions to replace a positively-charged amino acid with anegatively-charged amino acid. For instance, in one embodiment, the CH3domain of HC1 or the CH3 domain of HC2 comprises an amino acid sequencediffering from a wild-type IgG amino acid sequence such that one or morepositively-charged amino acids (e.g., lysine, histidine and arginine) inthe wild-type human IgG amino acid sequence are replaced with one ormore negatively-charged amino acids (e.g., aspartic acid and glutamicacid) at the corresponding position(s) in the CH3 domain. In these andother embodiments, amino acids (e.g. lysine) at one or more positionsselected from 370, 392 and 409 (EU numbering system) are replaced with anegatively-charged amino acid (e.g., aspartic acid and glutamic acid).Unless indicated otherwise, throughout the present specification andclaims, the numbering of the residues in an immunoglobulin heavy chainor light chain is according to Kabat-EU numbering as described in Kabatet al., Sequences of Proteins of Immunological Interest, 5th Ed. PublicHealth Service, National Institutes of Health, Bethesda, Md. (1991). Anamino acid substitution in an amino acid sequence is typicallydesignated herein with a one-letter abbreviation for the amino acidresidue in a particular position, followed by the numerical amino acidposition relative to an original sequence of interest, which is thenfollowed by the one-letter symbol for the amino acid residue substitutedin. For example, “T30D” symbolizes a substitution of a threonine residueby an aspartate residue at amino acid position 30, relative to theoriginal sequence of interest. Another example, “S218G” symbolizes asubstitution of a serine residue by a glycine residue at amino acidposition 218, relative to the original amino acid sequence of interest.

In certain embodiments, HC1 or HC2 of the heterodimeric antibodies maycomprise one or more amino acid substitutions to replace anegatively-charged amino acid with a positively-charged amino acid. Forinstance, in one embodiment, the CH3 domain of HC1 or the CH3 domain ofHC2 comprises an amino acid sequence differing from wild-type IgG aminoacid sequence such that one or more negatively-charged amino acids inthe wild-type human IgG amino acid sequence are replaced with one ormore positively-charged amino acids at the corresponding position(s) inthe CH3 domain. In these and other embodiments, amino acids (e.g.,aspartic acid or glutamic acid) at one or more positions selected from356, 357, and 399 (EU numbering system) of the CH3 domain are replacedwith a positively-charged amino acid (e.g., lysine, histidine andarginine).

In particular embodiments, the heterodimeric antibody comprises a firstheavy chain comprising negatively-charged amino acids at positions 392and 409 (e.g., K392D and K409D substitutions), and a second heavy chaincomprising positively-charged amino acids at positions 356 and 399(e.g., E356K and D399K substitutions). In other particular embodiments,the heterodimeric antibody comprises a first heavy chain comprisingnegatively-charged amino acids at positions 392, 409, and 370 (e.g.,K392D, K409D, and K370D substitutions), and a second heavy chaincomprising positively-charged amino acids at positions 356, 399, and 357(e.g., E356K, D399K, and E357K substitutions). In related embodiments,the first heavy chain is from an anti-CGRP receptor antibody and thesecond heavy chain is from an anti-PAC1 receptor antibody. In otherrelated embodiments, the first heavy chain is from an anti-PAC1 receptorantibody and the second heavy chain is from an anti-CGRP receptorantibody.

To facilitate the association of a particular heavy chain with itscognate light chain, both the heavy and light chains may containcomplimentary amino acid substitutions. As used herein, “complimentaryamino acid substitutions” refer to a substitution to apositively-charged amino acid in one chain paired with anegatively-charged amino acid substitution in the other chain.

For example, in some embodiments, the heavy chain comprises at least oneamino acid substitution to introduce a charged amino acid and thecorresponding light chain comprises at least one amino acid substitutionto introduce a charged amino acid, wherein the charged amino acidintroduced into the heavy chain has the opposite charge of the aminoacid introduced into the light chain. In certain embodiments, one ormore positively-charged residues (e.g., lysine, histidine or arginine)can be introduced into a first light chain (LC1) and one or morenegatively-charged residues (e.g., aspartic acid or glutamic acid) canbe introduced into the companion heavy chain (HC1) at the bindinginterface of LC1/HC1, whereas one or more negatively-charged residues(e.g., aspartic acid or glutamic acid) can be introduced into a secondlight chain (LC2) and one or more positively-charged residues (e.g.,lysine, histidine or arginine) can be introduced into the companionheavy chain (HC2) at the binding interface of LC2/HC2. The electrostaticinteractions will direct the LC1 to pair with HC1 and LC2 to pair withHC2, as the opposite charged residues (polarity) at the interfaceattract. The heavy/light chain pairs having the same charged residues(polarity) at an interface (e.g. LC1/HC2 and LC2/HC1) will repel,resulting in suppression of the unwanted HC/LC pairings.

In these and other embodiments, the CH1 domain of the heavy chain or theCL domain of the light chain comprises an amino acid sequence differingfrom wild-type IgG amino acid sequence such that one or morepositively-charged amino acids in wild-type IgG amino acid sequence isreplaced with one or more negatively-charged amino acids. Alternatively,the CH1 domain of the heavy chain or the CL domain of the light chaincomprises an amino acid sequence differing from wild-type IgG amino acidsequence such that one or more negatively-charged amino acids inwild-type IgG amino acid sequence is replaced with one or morepositively-charged amino acids. In some embodiments, one or more aminoacids in the CH1 domain of the first and/or second heavy chain in theheterodimeric antibody at an EU position selected from F126, P127, L128,A141, L145, K147, D148, H168, F170, P171, V173, Q175, S176, S183, V185and K213 is replaced with a charged amino acid. In certain embodiments,a preferred residue for substitution with a negatively- orpositively-charged amino acid is S183 (EU numbering system). In someembodiments, S183 is substituted with a positively-charged amino acid.In alternative embodiments, S183 is substituted with anegatively-charged amino acid. For instance, in one embodiment, S183 issubstituted with a negatively-charged amino acid (e.g. S183E) in thefirst heavy chain, and S183 is substituted with a positively-chargedamino acid (e.g. S183K) in the second heavy chain.

In embodiments in which the light chain is a kappa light chain, one ormore amino acids in the CL domain of the first and/or second light chainin the heterodimeric antibody at a position (EU and Kabat numbering in akappa light chain) selected from F116, F118, S121, D122, E123, Q124,S131, V133, L135, N137, N138, Q160, S162, T164, S174 and S176 isreplaced with a charged amino acid. In embodiments in which the lightchain is a lambda light chain, one or more amino acids in the CL domainof the first and/or second light chain in the heterodimeric antibody ata position (Kabat numbering in a lambda chain) selected from T116, F118,S121, E123, E124, K129, T131, V133, L135, S137, E160, T162, S165, Q167,A174, S176 and Y178 is replaced with a charged amino acid. In someembodiments, a preferred residue for substitution with a negatively- orpositively-charged amino acid is S176 (EU and Kabat numbering system) ofthe CL domain of either a kappa or lambda light chain. In certainembodiments, S176 of the CL domain is replaced with a positively-chargedamino acid. In alternative embodiments, S176 of the CL domain isreplaced with a negatively-charged amino acid. In one embodiment, S176is substituted with a positively-charged amino acid (e.g. S176K) in thefirst light chain, and S176 is substituted with a negatively-chargedamino acid (e.g. S176E) in the second light chain.

In addition to or as an alternative to the complimentary amino acidsubstitutions in the CH1 and CL domains, the variable regions of thelight and heavy chains in the heterodimeric antibody may contain one ormore complimentary amino acid substitutions to introduce charged aminoacids. For instance, in some embodiments, the VH region of the heavychain or the VL region of the light chain of a heterodimeric antibodycomprises an amino acid sequence differing from wild-type IgG amino acidsequence such that one or more positively-charged amino acids inwild-type IgG amino acid sequence is replaced with one or morenegatively-charged amino acids. Alternatively, the VH region of theheavy chain or the VL region of the light chain comprises an amino acidsequence differing from wild-type IgG amino acid sequence such that oneor more negatively-charged amino acids in wild-type IgG amino acidsequence is replaced with one or more positively-charged amino acids.

V region interface residues (i.e., amino acid residues that mediateassembly of the VH and VL regions) within the VH region include Kabatpositions 1, 3, 35, 37, 39, 43, 44, 45, 46, 47, 50, 59, 89, 91, and 93.One or more of these interface residues in the VH region can besubstituted with a charged (positively- or negatively-charged) aminoacid. In certain embodiments, the amino acid at Kabat position 39 in theVH region of the first and/or second heavy chain is substituted for apositively-charged amino acid, e.g., lysine. In alternative embodiments,the amino acid at Kabat position 39 in the VH region of the first and/orsecond heavy chain is substituted for a negatively-charged amino acid,e.g., glutamic acid. In some embodiments, the amino acid at Kabatposition 39 in the VH region of the first heavy chain is substituted fora negatively-charged amino acid (e.g. G39E), and the amino acid at Kabatposition 39 in the VH region of the second heavy chain is substitutedfor a positively-charged amino acid (e.g. G39K). In some embodiments,the amino acid at Kabat position 44 in the VH region of the first and/orsecond heavy chain is substituted for a positively-charged amino acid,e.g., lysine. In alternative embodiments, the amino acid at Kabatposition 44 in the VH region of the first and/or second heavy chain issubstituted for a negatively-charged amino acid, e.g., glutamic acid. Incertain embodiments, the amino acid at Kabat position 44 in the VHregion of the first heavy chain is substituted for a negatively-chargedamino acid (e.g. G44E), and the amino acid at Kabat position 44 in theVH region of the second heavy chain is substituted for apositively-charged amino acid (e.g. G44K).

V region interface residues (i.e., amino acid residues that mediateassembly of the VH and VL regions) within the VL region include Kabatpositions 32, 34, 35, 36, 38, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51,53, 54, 55, 56, 57, 58, 85, 87, 89, 90, 91, and 100. One or moreinterface residues in the VL region can be substituted with a chargedamino acid, preferably an amino acid that has an opposite charge tothose introduced into the VH region of the cognate heavy chain. In someembodiments, the amino acid at Kabat position 100 in the VL region ofthe first and/or second light chain is substituted for apositively-charged amino acid, e.g., lysine. In alternative embodiments,the amino acid at Kabat position 100 in the VL region of the firstand/or second light chain is substituted for a negative-charged aminoacid, e.g., glutamic acid. In certain embodiments, the amino acid atKabat position 100 in the VL region of the first light chain issubstituted for a positively-charged amino acid (e.g. G100K), and theamino acid at Kabat position 100 in the VL region of the second lightchain is substituted for a negatively-charged amino acid (e.g. G100E).

In certain embodiments, a heterodimeric antibody of the inventioncomprises a first heavy chain and a second heavy chain and a first lightchain and a second light chain, wherein the first heavy chain comprisesamino acid substitutions at positions 44 (Kabat), 183 (EU), 392 (EU) and409 (EU), wherein the second heavy chain comprises amino acidsubstitutions at positions 44 (Kabat), 183 (EU), 356 (EU) and 399 (EU),wherein the first and second light chains comprise an amino acidsubstitution at positions 100 (Kabat) and 176 (EU), and wherein theamino acid substitutions introduce a charged amino acid at saidpositions. In related embodiments, the glycine at position 44 (Kabat) ofthe first heavy chain is replaced with glutamic acid, the glycine atposition 44 (Kabat) of the second heavy chain is replaced with lysine,the glycine at position 100 (Kabat) of the first light chain is replacedwith lysine, the glycine at position 100 (Kabat) of the second lightchain is replaced with glutamic acid, the serine at position 176 (EU) ofthe first light chain is replaced with lysine, the serine at position176 (EU) of the second light chain is replaced with glutamic acid, theserine at position 183 (EU) of the first heavy chain is replaced withglutamic acid, the lysine at position 392 (EU) of the first heavy chainis replaced with aspartic acid, the lysine at position 409 (EU) of thefirst heavy chain is replaced with aspartic acid, the serine at position183 (EU) of the second heavy chain is replaced with lysine, the glutamicacid at position 356 (EU) of the second heavy chain is replaced withlysine, and/or the aspartic acid at position 399 (EU) of the secondheavy chain is replaced with lysine.

In other embodiments, a heterodimeric antibody of the inventioncomprises a first heavy chain and a second heavy chain and a first lightchain and a second light chain, wherein the first heavy chain comprisesamino acid substitutions at positions 183 (EU), 392 (EU) and 409 (EU),wherein the second heavy chain comprises amino acid substitutions atpositions 183 (EU), 356 (EU) and 399 (EU), wherein the first and secondlight chains comprise an amino acid substitution at position 176 (EU),and wherein the amino acid substitutions introduce a charged amino acidat said positions. In related embodiments, the serine at position 176(EU) of the first light chain is replaced with lysine, the serine atposition 176 (EU) of the second light chain is replaced with glutamicacid, the serine at position 183 (EU) of the first heavy chain isreplaced with glutamic acid, the lysine at position 392 (EU) of thefirst heavy chain is replaced with aspartic acid, the lysine at position409 (EU) of the first heavy chain is replaced with aspartic acid, theserine at position 183 (EU) of the second heavy chain is replaced withlysine, the glutamic acid at position 356 (EU) of the second heavy chainis replaced with lysine, and/or the aspartic acid at position 399 (EU)of the second heavy chain is replaced with lysine.

In still other embodiments, a heterodimeric antibody of the inventioncomprises a first heavy chain and a second heavy chain and a first lightchain and a second light chain, wherein the first heavy chain comprisesamino acid substitutions at positions 183 (EU), 392 (EU), 409 (EU), and370 (EU), wherein the second heavy chain comprises amino acidsubstitutions at positions 183 (EU), 356 (EU), 399 (EU), and 357 (EU),wherein the first and second light chains comprise an amino acidsubstitution at position 176 (EU), and wherein the amino acidsubstitutions introduce a charged amino acid at said positions. Inrelated embodiments, the serine at position 176 (EU) of the first lightchain is replaced with lysine, the serine at position 176 (EU) of thesecond light chain is replaced with glutamic acid, the serine atposition 183 (EU) of the first heavy chain is replaced with glutamicacid, the lysine at position 392 (EU) of the first heavy chain isreplaced with aspartic acid, the lysine at position 409 (EU) of thefirst heavy chain is replaced with aspartic acid, the lysine at position370 (EU) of the first heavy chain is replaced with aspartic acid, theserine at position 183 (EU) of the second heavy chain is replaced withlysine, the glutamic acid at position 356 (EU) of the second heavy chainis replaced with lysine, the aspartic acid at position 399 (EU) of thesecond heavy chain is replaced with lysine, and/or the glutamic acid atposition 357 (EU) of the second heavy chain is replaced with lysine.

Any of the constant domains, anti-PAC1 receptor variable regions, andanti-CGRP receptor variable regions described herein can be modified tocontain one or more of the charge pair mutations described above tofacilitate correct assembly of a heterodimeric antibody.

Exemplary full-length light chain sequences and full-length heavy chainsequences from anti-PAC1 receptor antibodies containing one or morecharge pair mutations suitable for use in the heterodimeric antibodiesof the invention are shown in Table 6A and Table 6B, respectively.

TABLE 6A Exemplary Anti-PAC1 Receptor Light Chain Sequences Antibody LCLight Chain Amino Light Chain Nucleic ID. Group Acid SequenceAcid Sequence 01A, 01C, LC-01 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC 01D SQSISRYLNWYQQKPGKAPKLLIYTGTCTGCATCTGTAGGAGACAGAATCACCA AASSLQSGIPSRFSGSGSGTDFTLTTCACTTGCCGGGCAAGTCAGAGCATTAGCA INSLQPEDFATYFCQQSYSPPFTFGGGTATTTAAATTGGTATCAACAGAAACCAG PGTKVDIKRTVAAPSVFIFPPSDEQGGAAAGCCCCTAAACTCCTGATCTATGCTG LKSGTASVVCLLNNFYPREAKVQCATCCAGTTTGCAAAGTGGGATCCCATCAA WKVDNALQSGNSQESVTEQDSKGGTTCAGCGGCAGTGGATCTGGGACAGATT DSTYSLESTLTLSKADYEKHKVYTCACTCTCACCATCAACAGTCTGCAACCTGA ACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGAGT (SEQ ID NO: 211)TACAGTCCCCCATTCACTTTCGGCCCTGGGA CCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGT GTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAGAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 222) 01B LC-02 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQSISRYLNWYQQKPGKAPKLLIYTGTCTGCATCTGTAGGAGACAGAATCACCA AASSLQSGIPSRFSGSGSGTDFTLTTCACTTGCCGGGCAAGTCAGAGCATTAGCA INSLQPEDFATYFCQQSYSPPFTFGGGTATTTAAATTGGTATCAACAGAAACCAG EGTKVDIKRTVAAPSVFIFPPSDEGGAAAGCCCCTAAACTCCTGATCTATGCTG QLKSGTASVVCLLNNFYPREAKVCATCCAGTTTGCAAAGTGGGATCCCATCAA QWKVDNALQSGNSQESVTEQDSGGTTCAGCGGCAGTGGATCTGGGACAGATT KDSTYSLESTLTLSKADYEKHKVTCACTCTCACCATCAACAGTCTGCAACCTGA YACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGAGT (SEQ ID NO: 212)TACAGTCCCCCATTCACTTTCGGCGAGGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAGAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 223) 02A, 02C LC-03 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQSISRYLNWYQQKPGKAPKLLIYTGTCTGCATCTGTAGGAGACAGAATCACCA AASSLQSGIPSRFSGSGSGTDFTLTTCACTTGCCGGGCAAGTCAGAGCATTAGCA INSLQPEDFATYFCQQSYSPPFTFGGGTATTTAAATTGGTATCAACAGAAACCAG QGTKVDIKRTVAAPSVFIFPPSDEGGAAAGCCCCTAAACTCCTGATCTATGCTG QLKSGTASVVCLLNNFYPREAKVCATCCAGTTTGCAAAGTGGGATCCCATCAA QWKVDNALQSGNSQESVTEQDSGGTTCAGCGGCAGTGGATCTGGGACAGATT KDSTYSLESTLTLSKADYEKHKVTCACTCTCACCATCAACAGTCTGCAACCTGA YACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGAGT (SEQ ID NO: 213)TACAGTCCCCCATTCACTTTCGGCCAGGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAAAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 224) 03A, 03C, LC-04 DIQLTQSPSFLSASVGDRVTITCRAGATATCCAGCTCACTCAATCGCCATCATTTC 03D SQSIGRSLHWYQQKPGKAPKLLIKTCTCCGCTTCGGTAGGCGACCGGGTCACGA YASQSLSGVPSRFSGSGSGTEFTLTCACATGCAGGGCGTCGCAAAGCATTGGGA TISSLQPEDFATYYCHQSSRLPFTFGGTCGTTGCATTGGTATCAGCAGAAACCCG GPGTKVDIKRTVAAPSVFIFPPSDEGAAAGGCCCCGAAACTTCTGATCAAATACG QLKSGTASVVCLLNNFYPREAKVCATCACAAAGCTTGAGCGGTGTGCCGTCGC QWKVDNALQSGNSQESVTEQDSGCTTCTCCGGTTCCGGAAGCGGAACGGAAT KDSTYSLESTLTLSKADYEKHKVTCACGCTTACAATCTCCTCACTGCAGCCCGA YACEVTHQGLSSPVTKSFNRGECGGATTTCGCGACCTATTACTGTCACCAGTCA (SEQ ID NO: 214)TCCAGACTCCCGTTTACTTTTGGCCCTGGGA CCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGT GTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAGAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 225) 03B LC-05 DIQLTQSPSFLSASVGDRVTITCRAGATATCCAGCTCACTCAATCGCCATCATTTC SQSIGRSLHWYQQKPGKAPKLLIKTCTCCGCTTCGGTAGGCGACCGGGTCACGA YASQSLSGVPSRFSGSGSGTEFTLTCACATGCAGGGCGTCGCAAAGCATTGGGA TISSLQPEDFATYYCHQSSRLPFTFGGTCGTTGCATTGGTATCAGCAGAAACCCG GEGTKVDIKRTVAAPSVFIFPPSDGAAAGGCCCCGAAACTTCTGATCAAATACG EQLKSGTASVVCLLNNFYPREAKCATCACAAAGCTTGAGCGGTGTGCCGTCGC VQWKVDNALQSGNSQESVTEQDGCTTCTCCGGTTCCGGAAGCGGAACGGAAT SKDSTYSLESTLTLSKADYEKHKTCACGCTTACAATCTCCTCACTGCAGCCCGA VYACEVTHQGLSSPVTKSFNRGEGGATTTCGCGACCTATTACTGTCACCAGTCA C (SEQ ID NO: 215)TCCAGACTCCCGTTTACTTTTGGCGAGGGGA CCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGT GTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAGAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 226) 04A, 04C, LC-06 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA 04D SQSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCCAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLESTLTLSKADYEKHKTCACGCTCACAATCTCCTCGCTGGAACCCG VYACEVTHQGLSSPVTKSFNRGEAGGACTTCGCGGTCTACTATTGTCATCAGTC C (SEQ ID NO: 216)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAGAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 227) 04B LC-07 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SQSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCCAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGEGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLESTLTLSKADYEKHKTCACGCTCACAATCTCCTCGCTGGAACCCG VYACEVTHQGLSSPVTKSFNRGEAGGACTTCGCGGTCTACTATTGTCATCAGTC C (SEQ ID NO: 217)ATCGAGGTTGCCTTTCACGTTTGGAGAAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAGAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 228) 05A, 05C, LC-08 DIVMTQSPDSLAVSLGERATIHCKGACATCGTGATGACCCAGTCTCCAGACTCC 05D SSQSVLYSSNNKNFLTWYQQKPGCTGGCTGTGTCTCTGGGCGAGAGGGCCACC QPPKLLIYRASTRESGVPDRFSGSATCCACTGCAAGTCCAGCCAGAGTGTTTTAT GSGTDFTLTISSLQAEDVAVYFCQACAGCTCCAACAATAAGAACTTCTTAACTT QYYSAPFTFGPGTRVDIKRTVAAPGGTACCAGCAGAAACCAGGACAGCCTCCTA SVFIFPPSDEQLKSGTASVVCLLNAACTTCTCATTTACCGGGCATCTACCCGGGA NFYPREAKVQWKVDNALQSGNSATCCGGGGTTCCTGACCGATTCAGTGGCAG QESV1EQDSKDSTYSLESTLTLSKCGGGTCTGGGACAGATTTCACTCTCACCATC ADYEKHKVYACEVTHQGLSSPVTAGCAGCCTGCAGGCTGAAGATGTGGCAGTT KSFNRGEC  TATTTCTGTCAGCAATATTATAGTGCTCCAT(SEQ ID NO: 218) TCACTTTCGGCCCTGGGACCAGAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTG AATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCG GGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAG AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTC ACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 229) 05B LC-09DIVMTQSPDSLAVSLGERATIHCK GACATCGTGATGACCCAGTCTCCAGACTCCSSQSVLYSSNNKNFLTWYQQKPG CTGGCTGTGTCTCTGGGCGAGAGGGCCACCQPPKLLIYRASTRESGVPDRFSGS ATCCACTGCAAGTCCAGCCAGAGTGTTTTATGSGTDFTLTISSLQAEDVAVYFCQ ACAGCTCCAACAATAAGAACTTCTTAACTTQYYSAPFTFGEGTRVDIKRTVAAP GGTACCAGCAGAAACCAGGACAGCCTCCTASVFIFPPSDEQLKSGTASVVCLLN AACTTCTCATTTACCGGGCATCTACCCGGGANFYPREAKVQWKVDNALQSGNS ATCCGGGGTTCCTGACCGATTCAGTGGCAGQESVTEQDSKDSTYSLESTLTLSK CGGGTCTGGGACAGATTTCACTCTCACCATCADYEKHKVYACEVTHQGLSSPVT AGCAGCCTGCAGGCTGAAGATGTGGCAGTT KSFNRGECTATTTCTGTCAGCAATATTATAGTGCTCCAT (SEQ ID NO: 219)TCACTTTCGGCGAGGGGACCAGAGTGGATA TCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTA CAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAG GACAGCAAGGACAGCACCTACAGCCTCGAGAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACA AAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 230)06A, 06C LC-10 DIVMTQSPDSLAVSLGERATINCK GACATCGTGATGACCCAGTCTCCAGACTCCSSQSVLYSSNNKNFLTWYQQKPG CTGGCTGTGTCTCTGGGCGAGAGGGCCACCQPPKLLIYRASTRESGVPDRFSGS ATCAACTGCAAGTCCAGCCAGAGTGTTTTAGSGTDFTLTISSLQAEDVAVYFCQ TACAGCTCCAACAATAAGAACTTCTTAACTTQYYSAPFTFGPGTRVDIKRTVAAP GGTACCAGCAGAAACCAGGACAGCCTCCTASVFIFPPSDEQLKSGTASVVCLLN AACTTCTCATTTACCGGGCATCTACCCGGGANFYPREAKVQWKVDNALQSGNS ATCCGGGGTTCCTGACCGATTCAGTGGCAGQESVTEQDSKDSTYSLESTLTLSK CGGGTCTGGGACAGATTTCACTCTCACCATCADYEKHKVYACEVTHQGLSSPVT AGCAGCCTGCAGGCTGAAGATGTGGCAGTT KSFNRGECTATTTCTGTCAGCAATATTATAGTGCTCCAT (SEQ ID NO: 220)TCACTTTCGGCCCTGGGACCAGAGTGGATA TCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTA CAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAG GACAGCAAGGACAGCACCTACAGCCTCGAAAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACA AAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 231)06B LC-11 DIVMTQSPDSLAVSLGERATINCK GACATCGTGATGACCCAGTCTCCAGACTCCSSQSVLYSSNNKNFLTWYQQKPG CTGGCTGTGTCTCTGGGCGAGAGGGCCACCQPPKLLIYRASTRESGVPDRFSGS ATCAACTGCAAGTCCAGCCAGAGTGTTTTAGSGTDFTLTISSLQAEDVAVYFCQ TACAGCTCCAACAATAAGAACTTCTTAACTTQYYSAPFTFGEGTRVDIKRTVAAP GGTACCAGCAGAAACCAGGACAGCCTCCTASVFIFPPSDEQLKSGTASVVCLLN AACTTCTCATTTACCGGGCATCTACCCGGGANFYPREAKVQWKVDNALQSGNS ATCCGGGGTTCCTGACCGATTCAGTGGCAGQESVTEQDSKDSTYSLESTLTLSK CGGGTCTGGGACAGATTTCACTCTCACCATCADYEKHKVYACEVTHQGLSSPVT AGCAGCCTGCAGGCTGAAGATGTGGCAGTT KSFNRGECTATTTCTGTCAGCAATATTATAGTGCTCCAT (SEQ ID NO: 221)TCACTTTCGGCGAGGGGACCAGAGTGGATA TCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTA CAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAG GACAGCAAGGACAGCACCTACAGCCTCGAAAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACA AAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 232)

TABLE 6B  Exemplary Anti-PAC1 Receptor Heavy Chain Sequences Antibody HCHeavy Chain Amino Acid ID. Group SequenceHeavy Chain Nucleic Acid Sequence 01A, 02A HC-01 QVQLQQSGPGLVKPSQTLCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGT SLTCAISGDSVSSNSATWGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCAT NWIRQSPSRGLEWLGRTYCTCCGGGGACAGTGTCTCTAGCAACAGTGCTACTTG YRSKWSNHYAVSVKSRITGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTG INPDTSKSQFSLQLNSVTPAGTGGCTGGGAAGGACATATTACAGGTCCAAGTGG EDTAVYYCARGTWKQLTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATA WFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCC STKGPSVFPLAPSSKSTSGCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCT GTAALGCLVKDYFPEPVTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCT VSWNSGALTSGVHTFPAATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGT VLQSSGLYSLKSVVTVPSCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGT SSLGTQTYICNVNHKPSNCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG TKVDKKVEPKSCDKTHTGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT CPPCPAPELLGGPSVFLFPACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA PKPKDTLMISRTPEVTCVGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT VVDVSHEDPEVKFNWYVGTCCTACAGTCCTCAGGACTCTACTCCCTCAAGAGC DGVEVHNAKTKPCEEQYGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GSTYRCVSVLTVLHQDWGACCTACATCTGCAACGTGAATCACAAGCCCAGCA LNGKEYKCKVSNKALPAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCT PIEKTISKAKGQPREPQVYTGTGACAAAACTCACACATGCCCACCGTGCCCAGC TLPPSREEMTKNQVSLTCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTT LVKGFYPSDIAVEWESNGCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCG QPENNYDTTPPVLDSDGSGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA FFLYSDLTVDKSRWQQGGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC NVFSCSVMHEALHNHYTGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA QKSLSLSPGK (SEQ IDGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTT NO: 233)GTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC TGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAA TGGGCAGCCGGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA GCGATCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 252) 01B HC-02 QVQLQQSGPGLVKPSQTLCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGT SLTCAISGDSVSSNSATWGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCAT NWIRQSPSRKLEWLGRTYCTCCGGGGACAGTGTCTCTAGCAACAGTGCTACTTG YRSKWSNHYAVSVKSRITGAACTGGATCAGGCAGTCCCCATCGAGAAAGCTTG INPDTSKSQFSLQLNSVTPAGTGGCTGGGAAGGACATATTACAGGTCCAAGTGG EDTAVYYCARGTWKQLTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATA WFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCC STKGPSVFPLAPSSKSTSGCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCT GTAALGCLVKDYFPEPVTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCT VSWNSGALTSGVHTFPAATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGT VLQSSGLYSLKSVVTVPSCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGT SSLGTQTYICNVNHKPSNCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG TKVDKKVEPKSCDKTHTGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT CPPCPAPELLGGPSVFLFPACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA PKPKDTLMISRTPEVTCVGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT VVDVSHEDPEVKFNWYVGTCCTACAGTCCTCAGGACTCTACTCCCTCAAGAGC DGVEVHNAKTKPCEEQYGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GSTYRCVSVLTVLHQDWGACCTACATCTGCAACGTGAATCACAAGCCCAGCA LNGKEYKCKVSNKALPAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCT PIEKTISKAKGQPREPQVYTGTGACAAAACTCACACATGCCCACCGTGCCCAGC TLPPSREEMTKNQVSLTCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTT LVKGFYPSDIAVEWESNGCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCG QPENNYDTTPPVLDSDGSGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA FFLYSDLTVDKSRWQQGGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC NVFSCSVMHEALHNHYTGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA QKSLSLSPGK (SEQ IDGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTT NO: 234)GTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC TGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAA TGGGCAGCCGGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA GCGATCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 253) 01C, 02C HC-03 QVQLQQSGPGLVKPSQTLCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGT SLTCAISGDSVSSNSATWGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCAT NWIRQSPSRGLEWLGRTYCTCCGGGGACAGTGTCTCTAGCAACAGTGCTACTTG YRSKWSNHYAVSVKSRITGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTG INPDTSKSQFSLQLNSVTPAGTGGCTGGGAAGGACATATTACAGGTCCAAGTGG EDTAVYYCARGTWKQLTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATA WFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCC STKGPSVFPLAPSSKSTSGCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCT GTAALGCLVKDYFPEPVTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCT VSWNSGALTSGVHTFPAATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGT VLQSSGLYSLKSVVTVPSCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGT SSLGTQTYICNVNHKPSNCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG TKVDKKVEPKSCDKTHTGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT CPPCPAPELLGGPSVFLFPACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA PKPKDTLMISRTPEVTCVGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT VVDVSHEDPEVKFNWYVGTCCTACAGTCCTCAGGACTCTACTCCCTCAAGAGC DGVEVHNAKTKPCEEQYGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GSTYRCVSVLTVLHQDWGACCTACATCTGCAACGTGAATCACAAGCCCAGCA LNGKEYKCKVSNKALPAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCT PIEKTISKAKGQPREPQVYTGTGACAAAACTCACACATGCCCACCGTGCCCAGC TLPPSREEMTKNQVSLTCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTT LVDGFYPSDIAVEWESNGCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCG QPENNYDTTPPVLDSDGSGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA FFLYSDLTVDKSRWQQGGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC NVFSCSVMHEALHNHYTGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA QKSLSLSPGK (SEQ IDGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTT NO: 235)GTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC TGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG AACCAGGTCAGCCTGACCTGCCTGGTCGATGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAA TGGGCAGCCGGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA GCGATCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 254) 01D HC-04 QVQLQQSGPGLVKPSQTLCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGT SLTCAISGDSVSSNSATWGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCAT NWIRQSPSRGLEWLGRTYCTCCGGGGACAGTGTCTCTAGCAACAGTGCTACTTG YRSKWSNHYAVSVKSRITGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTG INPDTSKSQFSLQLNSVTPAGTGGCTGGGAAGGACATATTACAGGTCCAAGTGG EDTAVYYCARGTWKQLTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATA WFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCC STKGPSVFPLAPCSRSTSECTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCT STAALGCLVKDYFPEPVTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCT VSWNSGALTSGVHTFPAATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGT VLQSSGLYSLKSVVTVPSCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGT SNFGTQTYTCNVDHKPSNCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGA TKVDKTVERKCCVECPPCGAGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT PAPPVAGPSVFLFPPKPKDACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA TLMISRTPEVTCVVVDVSGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCT HEDPEVQFNWYVDGVEVGTCCTACAGTCCTCAGGACTCTACTCCCTCAAGAGC HNAKTKPREEQFNSTFRVGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAG VSVLTVVHQDWLNGKEYACCTACACCTGCAACGTAGATCACAAGCCCAGCAA KCKVSNKGLPAPIEKTISKCACCAAGGTGGACAAGACAGTTGAGCGCAAATGTT TKGQPREPQVYTLPPSREGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGTGG EMTKNQVSLTCLVDGFYCAGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA PSDIAVEWESNGQPENNYAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA DTTPPMLDSDGSFFLYSDCGTGCGTGGTGGTGGACGTGAGCCACGAAGACCCC LTVDKSRWQQGNVFSCSGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGA VMHEALHNHYTQKSLSLGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGC SPGK (SEQ ID NO: 236)AGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCA CCGTTGTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGC CCCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCA TCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCGATGGCTTCTACCCCAGCGACAT CGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGATACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCGATCTCACCGTGG ACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC ACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA(SEQ ID NO: 255) 03A HC-05 QVQLVESGAEVVKPGASCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGT VKVSCKASGFTFSRFAMHAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAG WVRQAPGQGLEWMGVISCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATT YDGGNKYYAESVKGRVTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGG MTRDTSTSTLYMELSSLRATGGGAGTTATTAGCTATGACGGGGGCAATAAGTA SEDTAVYYCARGYDVLTCTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGA GYPDYWGQGTLVTVSSACACGGGACACCTCAACCAGTACACTCTATATGGAA STKGPSVFPLAPSSKSTSGCTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTAT GTAALGCLVKDYFPEPVTTATTGCGCTAGGGGGTACGATGTATTGACGGGTTAT VSWNSGALTSGVHTFPACCTGATTACTGGGGGCAGGGGACACTCGTAACCGT VLQSSGLYSLKSVVTVPSCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCC SSLGTQTYICNVNHKPSNCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC TKVDKKVEPKSCDKTHTAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CPPCPAPELLGGPSVFLFPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC PKPKDTLMISRTPEVTCVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VVDVSHEDPEVKFNWYVAGTCCTCAGGACTCTACTCCCTCAAGAGCGTGGTGA DGVEVHNAKTKPCEEQYCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA GSTYRCVSVLTVLHQDWTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG LNGKEYKCKVSNKALPAGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA PIEKTISKAKGQPREPQVYAACTCACACATGCCCACCGTGCCCAGCACCTGAACT TLPPSREEMTKNQVSLTCCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA LVKGFYPSDIAVEWESNGACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA QPENNYDTTPPVLDSDGSGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FFLYSDLTVDKSRWQQGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC NVFSCSVMHEALHNHYTGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGA QKSLSLSPGK (SEQ IDGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG NO: 237)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 256) 03B HC-06QVQLVESGAEVVKPGAS CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGT VKVSCKASGFTFSRFAMHAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAG WVRQAPGQKLEWMGVISCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATT YDGGNKYYAESVKGRVTGGGTGCGGCAAGCTCCCGGTCAGAAGTTGGAGTGG MTRDTSTSTLYMELSSLRATGGGAGTTATTAGCTATGACGGGGGCAATAAGTA SEDTAVYYCARGYDVLTCTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGA GYPDYWGQGTLVTVSSACACGGGACACCTCAACCAGTACACTCTATATGGAA STKGPSVFPLAPSSKSTSGCTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTAT GTAALGCLVKDYFPEPVTTATTGCGCTAGGGGGTACGATGTATTGACGGGTTAT VSWNSGALTSGVHTFPACCTGATTACTGGGGGCAGGGGACACTCGTAACCGT VLQSSGLYSLKSVVTVPSCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCC SSLGTQTYICNVNHKPSNCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC TKVDKKVEPKSCDKTHTAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CPPCPAPELLGGPSVFLFPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC PKPKDTLMISRTPEVTCVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VVDVSHEDPEVKFNWYVAGTCCTCAGGACTCTACTCCCTCAAGAGCGTGGTGA DGVEVHNAKTKPCEEQYCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA GSTYRCVSVLTVLHQDWTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG LNGKEYKCKVSNKALPAGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA PIEKTISKAKGQPREPQVY AACTCACACATGCCCACCGTGCCCAGCACCTGAACT TLPPSREEMTKNQVSLTCCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA LVKGFYPSDIAVEWESNGACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA QPENNYDTTPPVLDSDGSGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FFLYSDLTVDKSRWQQGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC NVFSCSVMHEALHNHYTGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGA QKSLSLSPGK (SEQ IDGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG NO: 238)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 257) 03C HC-07QVQLVESGAEVVKPGAS CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGT VKVSCKASGFTFSRFAMHAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAG WVRQAPGQGLEWMGVISCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATT YDGGNKYYAESVKGRVTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGG MTRDTSTSTLYMELSSLRATGGGAGTTATTAGCTATGACGGGGGCAATAAGTA SEDTAVYYCARGYDVLTCTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGA GYPDYWGQGTLVTVSSACACGGGACACCTCAACCAGTACACTCTATATGGAA STKGPSVFPLAPSSKSTSGCTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTAT GTAALGCLVKDYFPEPVTTATTGCGCTAGGGGGTACGATGTATTGACGGGTTAT VSWNSGALTSGVHTFPACCTGATTACTGGGGGCAGGGGACACTCGTAACCGT VLQSSGLYSLKSVVTVPSCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCC SSLGTQTYICNVNHKPSNCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC TKVDKKVEPKSCDKTHTAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CPPCPAPELLGGPSVFLFPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC PKPKDTLMISRTPEVTCVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VVDVSHEDPEVKFNWYVAGTCCTCAGGACTCTACTCCCTCAAGAGCGTGGTGA DGVEVHNAKTKPCEEQYCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA GSTYRCVSVLTVLHQDWTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG LNGKEYKCKVSNKALPAGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA PIEKTISKAKGQPREPQVYAACTCACACATGCCCACCGTGCCCAGCACCTGAACT TLPPSREEMTKNQVSLTCCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA LVDGFYPSDIAVEWESNGACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA QPENNYDTTPPVLDSDGSGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FFLYSDLTVDKSRWQQGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC NVFSCSVMHEALHNHYTGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGA QKSLSLSPGK (SEQ IDGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG NO: 239)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCGATGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 258) 03D HC-08QVQLVESGAEVVKPGAS CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGT VKVSCKASGFTFSRFAMHAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAG WVRQAPGQGLEWMGVISCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATT YDGGNKYYAESVKGRVTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGG MTRDTSTSTLYMELSSLRATGGGAGTTATTAGCTATGACGGGGGCAATAAGTA SEDTAVYYCARGYDVLTCTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGA GYPDYWGQGTLVTVSSACACGGGACACCTCAACCAGTACACTCTATATGGAA STKGPSVFPLAPCSRSTSECTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTAT STAALGCLVKDYFPEPVTTATTGCGCTAGGGGGTACGATGTATTGACGGGTTAT VSWNSGALTSGVHTFPACCTGATTACTGGGGGCAGGGGACACTCGTAACCGT VLQSSGLYSLKSVVTVPSCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCC SNFGTQTYTCNVDHKPSNCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCA TKVDKTVERKCCVECPPCCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC PAPPVAGPSVFLFPPKPKDCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCT TLMISRTPEVTCVVVDVSCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTA HEDPEVQFNWYVDGVEVCAGTCCTCAGGACTCTACTCCCTCAAGAGCGTGGTG HNAKTKPREEQFNSTFRVACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTAC VSVLTVVHQDWLNGKEYACCTGCAACGTAGATCACAAGCCCAGCAACACCAA KCKVSNKGLPAPIEKTISKGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCG TKGQPREPQVYTLPPSREAGTGCCCACCGTGCCCAGCACCACCTGTGGCAGGA EMTKNQVSLTCLVDGFYCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC PSDIAVEWESNGQPENNYACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGC DTTPPMLDSDGSFFLYSDGTGGTGGTGGACGTGAGCCACGAAGACCCCGAGGT LTVDKSRWQQGNVFSCSCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGC VMHEALHNHYTQKSLSLATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTC SPGK (SEQ ID NO: 240)AACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTT GTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCCA TCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCGATGGCTTCTACCCCAGCGACATCGCCG TGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGATACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCGATCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 259) 04A HC-09QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT LRLSCAASGFTFSRFAMHCCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGC WVRQAPGKGLEWVAVISCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTG YDGGNKYYAESVKGRFTGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG ISRDNSKNTLYLQMNSLRTGGCAGTTATATCATATGATGGAGGAAATAAATAC AEDTALFYCARGYDVLTTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLKSVVTVPSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SSLGTQTYICNVNHKPSNCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC TKVDKKVEPKSCDKTHTAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CPPCPAPELLGGPSVFLFPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC PKPKDTLMISRTPEVTCVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VVDVSHEDPEVKFNWYVAGTCCTCAGGACTCTACTCCCTCAAGAGCGTGGTGA DGVEVHNAKTKPCEEQYCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA GSTYRCVSVLTVLHQDWTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG LNGKEYKCKVSNKALPAGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA PIEKTISKAKGQPREPQVYAACTCACACATGCCCACCGTGCCCAGCACCTGAACT TLPPSREEMTKNQVSLTCCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA LVKGFYPSDIAVEWESNGACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA QPENNYDTTPPVLDSDGSGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FFLYSDLTVDKSRWQQGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC NVFSCSVMHEALHNHYTGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGA QKSLSLSPGK (SEQ IDGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG NO: 241)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 260) 04B HC-10QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT LRLSCAASGFTFSRFAMHCCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGC WVRQAPGKKLEWVAVISCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTG YDGGNKYYAESVKGRFTGGTCCGCCAGGCTCCAGGCAAGAAGCTGGAGTGGG ISRDNSKNTLYLQMNSLRTGGCAGTTATATCATATGATGGAGGAAATAAATAC AEDTALFYCARGYDVLTTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLKSVVTVPSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SSLGTQTYICNVNHKPSNCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC TKVDKKVEPKSCDKTHTAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CPPCPAPELLGGPSVFLFPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC PKPKDTLMISRTPEVTCVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VVDVSHEDPEVKFNWYVAGTCCTCAGGACTCTACTCCCTCAAGAGCGTGGTGA DGVEVHNAKTKPCEEQYCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA GSTYRCVSVLTVLHQDWTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG LNGKEYKCKVSNKALPAGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA PIEKTISKAKGQPREPQVY AACTCACACATGCCCACCGTGCCCAGCACCTGAACT TLPPSREEMTKNQVSLTCCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA LVKGFYPSDIAVEWESNGACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA QPENNYDTTPPVLDSDGSGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FFLYSDLTVDKSRWQQGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC NVFSCSVMHEALHNHYTGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGA QKSLSLSPGK (SEQ IDGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG NO: 242)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 261) 04C HC-11QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT LRLSCAASGFTFSRFAMHCCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGC WVRQAPGKGLEWVAVISCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTG YDGGNKYYAESVKGRFTGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG ISRDNSKNTLYLQMNSLRTGGCAGTTATATCATATGATGGAGGAAATAAATAC AEDTALFYCARGYDVLTTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLKSVVTVPSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SSLGTQTYICNVNHKPSNCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC TKVDKKVEPKSCDKTHTAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CPPCPAPELLGGPSVFLFPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC PKPKDTLMISRTPEVTCVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VVDVSHEDPEVKFNWYVAGTCCTCAGGACTCTACTCCCTCAAGAGCGTGGTGA DGVEVHNAKTKPCEEQYCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA GSTYRCVSVLTVLHQDWTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG LNGKEYKCKVSNKALPAGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA PIEKTISKAKGQPREPQVYAACTCACACATGCCCACCGTGCCCAGCACCTGAACT TLPPSREEMTKNQVSLTCCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA LVDGFYPSDIAVEWESNGACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA QPENNYDTTPPVLDSDGSGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FFLYSDLTVDKSRWQQGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC NVFSCSVMHEALHNHYTGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGA QKSLSLSPGK (SEQ IDGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG NO: 243)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCGATGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 262) 04D HC-12QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGT LRLSCAASGFTFSRFAMHCCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGC WVRQAPGKGLEWVAVISCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTG YDGGNKYYAESVKGRFTGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG ISRDNSKNTLYLQMNSLRTGGCAGTTATATCATATGATGGAGGAAATAAATAC AEDTALFYCARGYDVLTTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPCSRSTSE GAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT STAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLKSVVTVPSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SNFGTQTYTCNVDHKPSNCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC TKVDKTVERKCCVECPPCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PAPPVAGPSVFLFPPKPKDCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTC TLMISRTPEVTCVVVDVSTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTAC HEDPEVQFNWYVDGVEVAGTCCTCAGGACTCTACTCCCTCAAGAGCGTGGTGA HNAKTKPREEQFNSTFRVCCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACA VSVLTVVHQDWLNGKEYCCTGCAACGTAGATCACAAGCCCAGCAACACCAAG KCKVSNKGLPAPIEKTISKGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGA TKGQPREPQVYTLPPSREGTGCCCACCGTGCCCAGCACCACCTGTGGCAGGAC EMTKNQVSLTCLVDGFYCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA PSDIAVEWESNGQPENNYCCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCG DTTPPMLDSDGSFFLYSDTGGTGGTGGACGTGAGCCACGAAGACCCCGAGGTC LTVDKSRWQQGNVFSCSCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA VMHEALHNHYTQKSLSLTAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCA SPGK (SEQ ID NO: 244)ACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTG TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGG AGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCGATGGCTTCTACCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGATACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCGATCTCACCGTGGACAAGA GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCA GAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ IDNO: 263) 05A HC-13 QVQLQESGPGLVKPSQTLCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGT SLTCTVSGGSISSGGYYWGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGT SWIRQHPGKGLEWIGYIYCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTG YSGNTYYNPSLKSRVTISGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGG GDTSKNQFSLKLRSVTAAAGTGGATTGGGTACATCTATTACAGTGGGAACACCT DTAVYYCTRGGAARGMACTACAACCCGTCCCTCAAGAGTCGAGTTACCATAT DVWGQGTTVTVSSASTKCAGGAGACACGTCTAAGAACCAGTTCTCCCTGAAG GPSVFPLAPSSKSTSGGTACTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTAT ALGCLVKDYFPEPVTVSTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGA WNSGALTSGVHTFPAVLCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTA QSSGLYSLKSVVTVPSSSLGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG GTQTYICNVNHKPSNTKVCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG DKKVEPKSCDKTHTCPPCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA PAPELLGGPSVFLFPPKPKCCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC DTLMISRTPEVTCVVVDVCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTC SHEDPEVKFNWYVDGVECTCAGGACTCTACTCCCTCAAGAGCGTGGTGACCGT VHNAKTKPCEEQYGSTYGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG RCVSVLTVLHQDWLNGKCAACGTGAATCACAAGCCCAGCAACACCAAGGTGG EYKCKVSNKALPAPIEKTIACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT SKAKGQPREPQVYTLPPSCACACATGCCCACCGTGCCCAGCACCTGAACTCCTG REEMTKNQVSLTCLVKGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC FYPSDIAVEWESNGQPENAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC NYDTTPPVLDSDGSFFLYACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SDLTVDKSRWQQGNVFSTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG CSVMHEALHNHYTQKSLAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAG SLSPGK (SEQ ID NO: 245)CAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCACCGTG GACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA(SEQ ID NO: 264) 05B HC-14 QVQLQESGPGLVKPSQTLCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGT SLTCTVSGGSISSGGYYWGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGT SWIRQHPGKKLEWIGYIYCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTG YSGNTYYNPSLKSRVTISGAGCTGGATCCGCCAGCACCCAGGGAAGAAGCTGG GDTSKNQFSLKLRSVTAAAGTGGATTGGGTACATCTATTACAGTGGGAACACCT DTAVYYCTRGGAARGMACTACAACCCGTCCCTCAAGAGTCGAGTTACCATAT DVWGQGTTVTVSSASTKCAGGAGACACGTCTAAGAACCAGTTCTCCCTGAAG GPSVFPLAPSSKSTSGGTACTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTAT ALGCLVKDYFPEPVTVSTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGA WNSGALTSGVHTFPAVLCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTA QSSGLYSLKSVVTVPSSSLGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG GTQTYICNVNHKPSNTKVCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG DKKVEPKSCDKTHTCPPCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA PAPELLGGPSVFLFPPKPKCCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC DTLMISRTPEVTCVVVDVCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTC SHEDPEVKFNWYVDGVECTCAGGACTCTACTCCCTCAAGAGCGTGGTGACCGT VHNAKTKPCEEQYGSTYGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG RCVSVLTVLHQDWLNGKCAACGTGAATCACAAGCCCAGCAACACCAAGGTGG EYKCKVSNKALPAPIEKTI ACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT SKAKGQPREPQVYTLPPSCACACATGCCCACCGTGCCCAGCACCTGAACTCCTG REEMTKNQVSLTCLVKGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC FYPSDIAVEWESNGQPENAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC NYDTTPPVLDSD GSFFLYACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SDLTVDKSRWQQGNVFSTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG CSVMHEALHNHYTQKSLAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAG SLSPGK (SEQ ID NO: 246)CAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCACCGTG GACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA(SEQ ID NO: 265) 05C HC-15 QVQLQESGPGLVKPSQTLCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGT SLTCTVSGGSISSGGYYWGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGT SWIRQHPGKGLEWIGYIYCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTG YSGNTYYNPSLKSRVTISGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGG GDTSKNQFSLKLRSVTAAAGTGGATTGGGTACATCTATTACAGTGGGAACACCT DTAVYYCTRGGAARGMACTACAACCCGTCCCTCAAGAGTCGAGTTACCATAT DVWGQGTTVTVSSASTKCAGGAGACACGTCTAAGAACCAGTTCTCCCTGAAG GPSVFPLAPSSKSTSGGTACTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTAT ALGCLVKDYFPEPVTVSTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGA WNSGALTSGVHTFPAVLCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTA QSSGLYSLKSVVTVPSSSLGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG GTQTYICNVNHKPSNTKVCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG DKKVEPKSCDKTHTCPPCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA PAPELLGGPSVFLFPPKPKCCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC DTLMISRTPEVTCVVVDVCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTC SHEDPEVKFNWYVDGVECTCAGGACTCTACTCCCTCAAGAGCGTGGTGACCGT VHNAKTKPCEEQYGSTYGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG RCVSVLTVLHQDWLNGKCAACGTGAATCACAAGCCCAGCAACACCAAGGTGG EYKCKVSNKALPAPIEKTIACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT SKAKGQPREPQVYTLPPSCACACATGCCCACCGTGCCCAGCACCTGAACTCCTG REEMTKNQVSLTCLVDGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC FYPSDIAVEWESNGQPENAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC NYDTTPPVLDSDGSFFLYACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SDLTVDKSRWQQGNVFSTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG CSVMHEALHNHYTQKSLAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAG SLSPGK (SEQ ID NO: 247)CAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCGATGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGATACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGATCTCACCGTG GACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA(SEQ ID NO: 266) 05D HC-16 QVQLQESGPGLVKPSQTLCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGT SLTCTVSGGSISSGGYYWGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGT SWIRQHPGKGLEWIGYIYCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTG YSGNTYYNPSLKSRVTISGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGG GDTSKNQFSLKLRSVTAAAGTGGATTGGGTACATCTATTACAGTGGGAACACCT DTAVYYCTRGGAARGMACTACAACCCGTCCCTCAAGAGTCGAGTTACCATAT DVWGQGTTVTVSSASTK CAGGAGACACGTCTAAGAACCAGTTCTCCCTGAAG GPSVFPLAPCSRSTSESTACTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTAT ALGCLVKDYFPEPVTVSTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGA WNSGALTSGVHTFPAVLCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTA QSSGLYSLKSVVTVPSSNGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG FGTQTYTCNVDHKPSNTCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCG KVDKTVERKCCVECPPCPGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA APPVAGPSVFLFPPKPKDCCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGAC TLMISRTPEVTCVVVDVSCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTC HEDPEVQFNWYVDGVEVCTCAGGACTCTACTCCCTCAAGAGCGTGGTGACCGT HNAKTKPREEQFNSTFRVGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTG VSVLTVVHQDWLNGKEYCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG KCKVSNKGLPAPIEKTISKACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGC TKGQPREPQVYTLPPSRECCACCGTGCCCAGCACCACCTGTGGCAGGACCGTC EMTKNQVSLTCLVDGFYAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT PSDIAVEWESNGQPENNYCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGT DTTPPMLDSDGSFFLYSDGGTGGACGTGAGCCACGAAGACCCCGAGGTCCAGT LTVDKSRWQQGNVFSCSTCAACTGGTACGTGGACGGCGTGGAGGTGCATAAT VMHEALHNHYTQKSLSLGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAG SPGK (SEQ ID NO: 248)CACGTTCCGTGTGGTCAGCGTCCTCACCGTTGTGCA CCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCCATCGAG AAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGG AGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCGATGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACGATACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCGATCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 267) 06A HC-17 QVQLQESGPGLVKPSETLCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGT SLTCTVSGGSISSGGYYWGAAGCCTTCAGAGACCCTGTCCCTCACCTGCACTGT SWIRQPPGKGLEWIGYIYCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTG YSGNTYYNPSLKSRVTISGAGCTGGATCCGCCAGCCCCCAGGGAAGGGCCTGG VDTSKNQFSLKLRSVTAAAGTGGATTGGGTACATCTATTACAGTGGGAACACCT DTAVYYCTRGGAARGMACTACAACCCGTCCCTCAAGAGTCGAGTTACCATAT DVWGQGTTVTVSSASTK CAGTGGACACGTCTAAGAACCAGTTCTCCCTGAAG GPSVFPLAPSSKSTSGGTACTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTAT ALGCLVKDYFPEPVTVSTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGA WNSGALTSGVHTFPAVLCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTA QSSGLYSLKSVVTVPSSSLGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG GTQTYICNVNHKPSNTKVCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG DKKVEPKSCDKTHTCPPCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA PAPELLGGPSVFLFPPKPKCCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC DTLMISRTPEVTCVVVDVCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTC SHEDPEVKFNWYVDGVECTCAGGACTCTACTCCCTCAAGAGCGTGGTGACCGT VHNAKTKPCEEQYGSTYGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG RCVSVLTVLHQDWLNGKCAACGTGAATCACAAGCCCAGCAACACCAAGGTGG EYKCKVSNKALPAPIEKTIACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT SKAKGQPREPQVYTLPPSCACACATGCCCACCGTGCCCAGCACCTGAACTCCTG REEMTKNQVSLTCLVKGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC FYPSDIAVEWESNGQPENAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC NYDTTPPVLDSDGSFFLYACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SDLTVDKSRWQQGNVFSTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG CSVMHEALHNHYTQKSLAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAG SLSPGK (SEQ ID NO: 249)CAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGACACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGACCTCACCGTG GACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA(SEQ ID NO: 268) 06B HC-18 QVQLQESGPGLVKPSETLCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGT SLTCTVSGGSISSGGYYWGAAGCCTTCAGAGACCCTGTCCCTCACCTGCACTGT SWIRQPPGKKLEWIGYIYCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTG YSGNTYYNPSLKSRVTISGAGCTGGATCCGCCAGCCCCCAGGGAAGAAGCTGG VDTSKNQFSLKLRSVTAAAGTGGATTGGGTACATCTATTACAGTGGGAACACCT DTAVYYCTRGGAARGMACTACAACCCGTCCCTCAAGAGTCGAGTTACCATAT DVWGQGTTVTVSSASTKCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAAG GPSVFPLAPSSKSTSGGTACTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTAT ALGCLVKDYFPEPVTVSTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGA WNSGALTSGVHTFPAVLCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTA QSSGLYSLKSVVTVPSSSLGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG GTQTYICNVNHKPSNTKVCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG DKKVEPKSCDKTHTCPPCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA PAPELLGGPSVFLFPPKPKCCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC DTLMISRTPEVTCVVVDVCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTC SHEDPEVKFNWYVDGVECTCAGGACTCTACTCCCTCAAGAGCGTGGTGACCGT VHNAKTKPCEEQYGSTYGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG RCVSVLTVLHQDWLNGKCAACGTGAATCACAAGCCCAGCAACACCAAGGTGG EYKCKVSNKALPAPIEKTIACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT SKAKGQPREPQVYTLPPSCACACATGCCCACCGTGCCCAGCACCTGAACTCCTG REEMTKNQVSLTCLVKGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC FYPSDIAVEWESNGQPENAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC NYDTTPPVLDSDGSFFLYACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SDLTVDKSRWQQGNVFSTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG CSVMHEALHNHYTQKSLAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAG SLSPGK (SEQ ID NO: 250)CAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGACACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGACCTCACCGTG GACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA(SEQ ID NO: 269) 06C HC-19 QVQLQESGPGLVKPSETLCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGT SLTCTVSGGSISSGGYYWGAAGCCTTCAGAGACCCTGTCCCTCACCTGCACTGT SWIRQPPGKGLEWIGYIYCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTG YSGNTYYNPSLKSRVTISGAGCTGGATCCGCCAGCCCCCAGGGAAGGGCCTGG VDTSKNQFSLKLRSVTAAAGTGGATTGGGTACATCTATTACAGTGGGAACACCT DTAVYYCTRGGAARGMACTACAACCCGTCCCTCAAGAGTCGAGTTACCATAT DVWGQGTTVTVSSASTKCAGTGGACACGTCTAAGAACCAGTTCTCCCTGAAG GPSVFPLAPSSKSTSGGTACTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTAT ALGCLVKDYFPEPVTVSTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGA WNSGALTSGVHTFPAVLCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTA QSSGLYSLKSVVTVPSSSLGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG GTQTYICNVNHKPSNTKVCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG DKKVEPKSCDKTHTCPPCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA PAPELLGGPSVFLFPPKPKCCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC DTLMISRTPEVTCVVVDVCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTC SHEDPEVKFNWYVDGVECTCAGGACTCTACTCCCTCAAGAGCGTGGTGACCGT VHNAKTKPCEEQYGSTYGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG RCVSVLTVLHQDWLNGKCAACGTGAATCACAAGCCCAGCAACACCAAGGTGG EYKCKVSNKALPAPIEKTIACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT SKAKGQPREPQVYTLPPSCACACATGCCCACCGTGCCCAGCACCTGAACTCCTG REEMTKNQVSLTCLVDGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC FYPSDIAVEWESNGQPENAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC NYDTTPPVLDSDGSFFLYACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SDLTVDKSRWQQGNVFSTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG CSVMHEALHNHYTQKSLAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAG SLSPGK (SEQ ID NO: 251)CAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCC ATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCGATGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACGACACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCGACCTCACCGTG GACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA(SEQ ID NO: 270)

In some embodiments, the heterodimeric antibody of the inventioncomprises an anti-PAC1 receptor light chain from Table 6A and ananti-PAC1 receptor heavy chain from Table 6B. Exemplary pairs ofanti-PAC1 receptor light and heavy chains that may be incorporated intoa heterodimeric antibody include, but are not limited to: LC-01 (SEQ IDNO: 211) and HC-01 (SEQ ID NO: 233); LC-02 (SEQ ID NO: 212) and HC-02(SEQ ID NO: 234); LC-01 (SEQ ID NO: 211) and HC-03 (SEQ ID NO: 235);LC-01 (SEQ ID NO: 211) and HC-04 (SEQ ID NO: 236); LC-03 (SEQ ID NO:213) and HC-01 (SEQ ID NO: 233); LC-03 (SEQ ID NO: 213) and HC-03 (SEQID NO: 235); LC-04 (SEQ ID NO: 214) and HC-05 (SEQ ID NO: 237); LC-05(SEQ ID NO: 215) and HC-06 (SEQ ID NO: 238); LC-04 (SEQ ID NO: 214) andHC-07 (SEQ ID NO: 239); LC-04 (SEQ ID NO: 214) and HC-08 (SEQ ID NO:240); LC-06 (SEQ ID NO: 216) and HC-09 (SEQ ID NO: 241); LC-07 (SEQ IDNO: 217) and HC-10 (SEQ ID NO: 242); LC-06 (SEQ ID NO: 216) and HC-11(SEQ ID NO: 243); LC-06 (SEQ ID NO: 216) and HC-12 (SEQ ID NO: 244);LC-08 (SEQ ID NO: 218) and HC-13 (SEQ ID NO: 245); LC-09 (SEQ ID NO:219) and HC-14 (SEQ ID NO: 246); LC-08 (SEQ ID NO: 218) and HC-15 (SEQID NO: 247); LC-08 (SEQ ID NO: 218) and HC-16 (SEQ ID NO: 248); LC-10(SEQ ID NO: 220) and HC-17 (SEQ ID NO: 249); LC-11(SEQ ID NO: 221) andHC-18 (SEQ ID NO: 250); and LC-10 (SEQ ID NO: 220) and HC-19 (SEQ ID NO:251).

The anti-PAC1 receptor light chain and/or heavy chain incorporated intoa heterodimeric antibody of the invention may comprise a sequence ofcontiguous amino acids that differs from the sequence of a light chainin Table 6A or a heavy chain in Table 6B by 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15 or more amino acid residues, wherein each suchsequence difference is independently a deletion, insertion orsubstitution of one amino acid. In some embodiments, the anti-PAC1receptor light chain incorporated into a heterodimeric antibodycomprises a sequence of amino acids that has at least 70%, at least 75%,at least 80%, at least 85%, at least 90%, at least 95%, at least 97% orat least 99% sequence identity to the amino acid sequences of SEQ IDNOs: 211-221 (i.e. the anti-PAC1 receptor light chains in Table 6A). Incertain embodiments, the anti-PAC1 receptor heavy chain incorporatedinto a heterodimeric antibody comprises a sequence of amino acids thathas at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95%, at least 97% or at least 99% sequence identity to theamino acid sequences of SEQ ID NOs: 233-251 (i.e. the anti-PAC1 receptorheavy chains in Table 6B).

Exemplary full-length light chain sequences and full-length heavy chainsequences from anti-CGRP receptor antibodies containing one or morecharge pair mutations suitable for use in the heterodimeric antibodiesof the invention are shown in Table 7A and Table 7B, respectively.

TABLE 7A  Exemplary Anti-CGRP Receptor Light Chain Sequences Antibody LCLight Chain Amino Acid ID. Group SequenceLight Chain Nucleic Acid Sequence 50A, 50C, LC-101 QSVLTQPPSASGTPGQRVTICAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGG 50D SCSGSSSNIGSNYVYWYQQGACCCCCGGGCAGAGAGTCACCATCTCTTGTTCT LPGAAPKLLIFRNNQRPSGVGGAAGCAGCTCCAACATCGGCAGTAATTATGTAT PDRFSGSKSGTSASLAISGLACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAA RSEDEADYYCAAWDDSLSACTCCTCATCTTTAGGAATAATCAGCGGCCCTCAG GWVFGGGTKLTVLGQPKAGGGTCCCTGACCGCTTCTCTGGCTCCAAGTCTGGC NPTVTLFPPSSEELQANKATACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTC LVCLISDFYPGAVTVAWKACGAGGATGAGGCTGATTATTACTGTGCAGCATGG DGSPVKAGVETTKPSKQSNGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGAG NKYAAKSYLSLTPEQWKSHGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGC RSYSCQVTHEGSTVEKTVACAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTG PTECS (SEQ ID NO: 271)AGGAGCTCCAAGCCAACAAGGCCACACTAGTGTG TCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGG CGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGAG CCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCG TGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 283) 50B LC-102 QSVLTQPPSASGTPGQRVTICAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGG SCSGSSSNIGSNYVYWYQQGACCCCCGGGCAGAGAGTCACCATCTCTTGTTCT LPGAAPKLLIFRNNQRPSGVGGAAGCAGCTCCAACATCGGCAGTAATTATGTAT PDRFSGSKSGTSASLAISGLACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAA RSEDEADYYCAAWDDSLSACTCCTCATCTTTAGGAATAATCAGCGGCCCTCAG GWVFGKGTKLTVLGQPKAGGGTCCCTGACCGCTTCTCTGGCTCCAAGTCTGGC NPTVTLFPPSSEELQANKATACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTC LVCLISDFYPGAVTVAWKACGAGGATGAGGCTGATTATTACTGTGCAGCATGG DGSPVKAGVETTKPSKQSNGATGACAGCCTGAGTGGTTGGGTGTTCGGCAAGG NKYAAKSYLSLTPEQWKSHGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGC RSYSCQVTHEGSTVEKTVACAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTG PTECS (SEQ ID NO: 272)AGGAGCTCCAAGCCAACAAGGCCACACTAGTGTG TCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGG CGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGAG CCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCG TGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 284) 51A, 51C, LC-103 QSVLTQSPSASGTPGQRVTICAGTCTGTGCTGACTCAGTCACCCTCAGCGTCTGG 51D SCSGSSSNIGSNYVYWYQQGACCCCCGGGCAGAGAGTCACCATCTCTTGTTCT LPGAAPKLLILRNNQRPSGVGGAAGCAGCTCCAACATCGGCAGTAATTATGTAT PDRFSGSKSGTSASLTISGLACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAA RSEDEADYYCAAWDDSLSACTCCTCATCCTTAGGAATAATCAGCGGCCCTCA GWVFGGGTKLTVLGQPKAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGG NPTVTLFPPSSEELQANKATCACCTCAGCCTCCCTGACCATCAGTGGGCTCCGGT LVCLISDFYPGAVTVAWKACCGAGGATGAGGCTGACTATTATTGTGCAGCATG DGSPVKAGVETTKPSKQSNGGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGA NKYAAKSYLSLTPEQWKSHGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGG RSYSCQVTHEGSTVEKTVACCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCT PTECS (SEQ ID NO: 273)GAGGAGCTCCAAGCCAACAAGGCCACACTAGTGT GTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGA GCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 285) 51B LC-104 QSVLTQSPSASGTPGQRVTICAGTCTGTGCTGACTCAGTCACCCTCAGCGTCTGG SCSGSSSNIGSNYVYWYQQGACCCCCGGGCAGAGAGTCACCATCTCTTGTTCT LPGAAPKLLILRNNQRPSGVGGAAGCAGCTCCAACATCGGCAGTAATTATGTAT PDRFSGSKSGTSASLTISGLACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAA RSEDEADYYCAAWDDSLSACTCCTCATCCTTAGGAATAATCAGCGGCCCTCA GWVFGKGTKLTVLGQPKAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGG NPTVTLFPPSSEELQANKATCACCTCAGCCTCCCTGACCATCAGTGGGCTCCGGT LVCLISDFYPGAVTVAWKACCGAGGATGAGGCTGACTATTATTGTGCAGCATG DGSPVKAGVETTKPSKQSNGGATGACAGCCTGAGTGGTTGGGTGTTCGGCAAG NKYAAKSYLSLTPEQWKSHGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGG RSYSCQVTHEGSTVEKTVACCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCT PTECS (SEQ ID NO: 274)GAGGAGCTCCAAGCCAACAAGGCCACACTAGTGT GTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGA GCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 286) 52A, 52C, LC-105 QSVLTQPPSVSAAPGQKVTICAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGC 52D, 53A, SCSGSSSNIGNNYVSWYQQGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCT 53C LPGTAPKLLIYDNNKRPSGIGGAAGCAGCTCCAACATTGGGAATAATTATGTAT PDRFSGSKSGTSTTLGITGLCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAA QTGDEADYYCGTWDSRLSACTCCTCATTTATGACAATAATAAGCGACCCTCA AVVFGGGTKLTVLGQPKAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGG NPTVTLFPPSSEELQANKATCACGTCAACCACCCTGGGCATCACCGGACTCCAG LVCLISDFYPGAVTVAWKAACTGGGGACGAGGCCGATTATTACTGCGGAACAT DGSPVKAGVETTKPSKQSNGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGG NKYAAKSYLSLTPEQWKSHAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG RSYSCQVTHEGSTVEKTVAGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTC PTECS (SEQ ID NO: 275)TGAGGAGCTCCAAGCCAACAAGGCCACACTAGTG TGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGA GCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 287) 52B, 53B LC-106 QSVLTQPPSVSAAPGQKVTICAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGC SCSGSSSNIGNNYVSWYQQGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCT LPGTAPKLLIYDNNKRPSGIGGAAGCAGCTCCAACATTGGGAATAATTATGTAT PDRFSGSKSGTSTTLGITGLCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAA QTGDEADYYCGTWDSRLSACTCCTCATTTATGACAATAATAAGCGACCCTCA AVVFGKGTKLTVLGQPKAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGG NPTVTLFPPSSEELQANKATCACGTCAACCACCCTGGGCATCACCGGACTCCAG LVCLISDFYPGAVTVAWKAACTGGGGACGAGGCCGATTATTACTGCGGAACAT DGSPVKAGVETTKPSKQSNGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCAA NKYAAKSYLSLTPEQWKSHGGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG RSYSCQVTHEGSTVEKTVAGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTC PTECS (SEQ ID NO: 276)TGAGGAGCTCCAAGCCAACAAGGCCACACTAGTG TGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGA GCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 288) 54A, 54C, LC-107 QSVLTQPPSVSAAPGQKVTICAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGC 56A, 56C SCSGSSSNIGNNYVSWYQQGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCT LPGTAPKLLIYDNNKRPSGIGGAAGCAGCTCCAACATTGGGAATAATTATGTAT PDRFSGSKSGTSATLGITGLCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAA QTGDEADYYCGTWDSRLSACTCCTCATTTATGACAATAATAAGCGACCCTCA AVVFGGGTKLTVLGQPKAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGG NPTVTLFPPSSEELQANKATCACGTCAGCCACCCTGGGCATCACCGGACTCCAG LVCLISDFYPGAVTVAWKAACTGGGGACGAGGCCGATTATTACTGCGGAACAT DGSPVKAGVETTKPSKQSNGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGG NKYAAKSYLSLTPEQWKSHAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG RSYSCQVTHEGSTVEKTVAGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTC PTECS (SEQ ID NO: 277)TGAGGAGCTCCAAGCCAACAAGGCCACACTAGTG TGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGA GCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 289) 54B, 56B LC-108 QSVLTQPPSVSAAPGQKVTICAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGC SCSGSSSNIGNNYVSWYQQGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCT LPGTAPKLLIYDNNKRPSGIGGAAGCAGCTCCAACATTGGGAATAATTATGTAT PDRFSGSKSGTSATLGITGLCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAA QTGDEADYYCGTWDSRLSACTCCTCATTTATGACAATAATAAGCGACCCTCA AVVFGKGTKLTVLGQPKAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGG NPTVTLFPPSSEELQANKATCACGTCAGCCACCCTGGGCATCACCGGACTCCAG LVCLISDFYPGAVTVAWKAACTGGGGACGAGGCCGATTATTACTGCGGAACAT DGSPVKAGVETTKPSKQSNGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCAA NKYAAKSYLSLTPEQWKSHGGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG RSYSCQVTHEGSTVEKTVAGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTC PTECS (SEQ ID NO: 278)TGAGGAGCTCCAAGCCAACAAGGCCACACTAGTG TGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGA GCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 290) 55A, 55C LC-109 QSVLTQPPSVSAAPGQKVTICAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGC SCSGSSSNIGNNYVSWYQQGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCT LPGTAPKLLIYDNNKRPSGIGGAAGCAGCTCCAACATTGGGAATAATTATGTAT PDRFSGSKSGTSATLAITGLCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAA QTGDEADYYCGTWDSRLSACTCCTCATTTATGACAATAATAAGCGACCCTCA AVVFGGGTKLTVLGQPKAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGG NPTVTLFPPSSEELQANKATCACGTCAGCCACCCTGGCCATCACCGGACTCCAG LVCLISDFYPGAVTVAWKAACTGGGGACGAGGCCGATTATTACTGCGGAACAT DGSPVKAGVETTKPSKQSNGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGG NKYAAKSYLSLTPEQWKSHAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG RSYSCQVTHEGSTVEKTVAGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTC PTECS (SEQ ID NO: 279)TGAGGAGCTCCAAGCCAACAAGGCCACACTAGTG TGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGA GCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 291) 55B LC-110 QSVLTQPPSVSAAPGQKVTICAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGC SCSGSSSNIGNNYVSWYQQGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCT LPGTAPKLLIYDNNKRPSGIGGAAGCAGCTCCAACATTGGGAATAATTATGTAT PDRFSGSKSGTSATLAITGL CCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAA QTGDEADYYCGTWDSRLSACTCCTCATTTATGACAATAATAAGCGACCCTCA AVVFGKGTKLTVLGQPKAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGG NPTVTLFPPSSEELQANKATCACGTCAGCCACCCTGGCCATCACCGGACTCCAG LVCLISDFYPGAVTVAWKAACTGGGGACGAGGCCGATTATTACTGCGGAACAT DGSPVKAGVETTKPSKQSNGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCAA NKYAAKSYLSLTPEQWKSHGGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG RSYSCQVTHEGSTVEKTVAGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTC PTECS (SEQ ID NO: 280)TGAGGAGCTCCAAGCCAACAAGGCCACACTAGTG TGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGA GCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACC GTGGAGAAGACAGTGGCCCCTACAGAATGTTCA(SEQ ID NO: 292) 57A, 57C, LC-111  EIVLTQSPGTLSLSPGERATGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGT 57D, 58A, LSCRASQSVSSGYLTWYQQCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGC 58C KPGQAPRLLIYGASSRATGIAGGGCCAGTCAGAGTGTTAGCAGCGGCTACTTAA PDRFSGSGSGTDFTLTISRLECCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAG PEDFAVYYCQQYGNSLSRFACTCCTCATCTATGGTGCATCCAGCAGGGCCACT GQGTKLEIKRTVAAPSVFIFGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTG PPSDEQLKSGTASVVCLLNGGACGGACTTCACTCTCACCATCAGCAGACTGGA NFYPREAKVQWKVDNALQGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGT SGNSQESVTEQDSKDSTYSATGGTAACTCACTGAGCAGGTTTGGCCAGGGGAC LKSTLTLSKADYEKHKVYACAAGCTGGAAATCAAACGTACGGTGGCTGCACCA CEVTHQGLSSPVTKSFNRGTCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTT EC (SEQ ID NO: 281)GAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGA ATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAAGAGCACCCTGACGCTGA GCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCC CGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 293) 57B, 58B  LC-112 EIVLTQSPGTLSLSPGERATGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGT LSCRASQSVSSGYLTWYQQCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGC KPGQAPRLLIYGASSRATGIAGGGCCAGTCAGAGTGTTAGCAGCGGCTACTTAA PDRFSGSGSGTDFTLTISRLECCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAG PEDFAVYYCQQYGNSLSRFACTCCTCATCTATGGTGCATCCAGCAGGGCCACT GKGTKLEIKRTVAAPSVFIFGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTG PPSDEQLKSGTASVVCLLNGTACGGACTTCACTCTCACCATCAGCAGACTGGA NFYPREAKVQWKVDNALQGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGT SGNSQESVTEQDSKDSTYSATGGTAACTCACTGAGCAGGTTTGGCAAGGGGAC LKSTLTLSKADYEKHKVYACAAGCTGGAGATCAAACGTACGGTGGCTGCACCA CEVTHQGLSSPVTKSFNRGTCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTT EC (SEQ ID NO: 282)GAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGA ATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAAGAGCACCCTGACGCTGA GCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCC CGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 294)

TABLE 7B  Exemplary Anti-CGRP Receptor Heavy Chain Sequences Antibody HCHeavy Chain Amino Acid Heavy Chain Nucleic Acid Sequence ID. GroupSequence 50A HC-101 EVQLVESGGGLVKPGGSLGAGGTACAGCTGGTGGAGTCTGGGGGAGGCTTGG RLSCAASGFTFGNAWMSTAAAGCCTGGGGGGTCCCTCAGACTCTCCTGTGC WVRQAPGKGLEWVGRIKSAGCCTCTGGATTCACTTTCGGTAACGCCTGGATGA KTDGGTTDYAAPVKGRFTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGA ISRDDSKNTLYLQMNSLKTGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGT EDTAVYFCTTDRTGYSISWGGGACAACAGACTACGCTGCACCCGTGAAAGGCA SSYYYYYGMDVWGQGTTGATTCACCATCTCAAGAGATGATTCAAAAAACAC VTVSSASTKGPSVFPLAPSGCTGTATCTGCAAATGAACAGCCTGAAAACCGAG SKSTSGGTAALGCLVKDYGACACAGCCGTGTATTTCTGTACCACAGATCGGA FPEPVTVSWNSGALTSGVCCGGGTATAGCATCAGCTGGTCTAGTTACTACTAC HTFPAVLQSSGLYSLESVVTACTACGGTATGGACGTCTGGGGCCAAGGAACAA TVPSSSLGTQTYICNVNHKCAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCC PSNTKVDKKVEPKSCDKTATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA HTCPPCPAPELLGGPSVFLCCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT FPPKPKDTLMISRTPEVTCCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG VVVDVSHEDPEVKFNWYTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA VDGVEVHNAKTKPCEEQYCCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC GSTYRCVSVLTVLHQDWLTCCCTCGAGAGCGTGGTGACCGTGCCCTCCAGCA NGKEYKCKVSNKALPAPIGCTTGGGCACCCAGACCTACATCTGCAACGTGAA EKTISKAKGQPREPQVYTLTCACAAGCCCAGCAACACCAAGGTGGACAAGAA PPSRKEMTKNQVSLTCLVAGTTGAGCCCAAATCTTGTGACAAAACTCACACA KGFYPSDIAVEWESNGQPETGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG NNYKTTPPVLKSDGSFFLYGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG SKLTVDKSRWQQGNVFSCGACACCCTCATGATCTCCCGGACCCCTGAGGTCA SVMHEALHNHYTQKSLSLCATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SPGK (SEQ ID NO: 295)TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CTCCCTGTCTCCGGGTAAA (SEQ ID NO: 317)50B HC-102 EVQLVESGGGLVKPGGSL GAGGTACAGCTGGTGGAGTCTGGGGGAGGCTTGGRLSCAASGFTFGNAWMS TAAAGCCTGGGGGGTCCCTCAGACTCTCCTGTGC WVRQAPGKELEWVGRIKSAGCCTCTGGATTCACTTTCGGTAACGCCTGGATGA KTDGGTTDYAAPVKGRFTGCTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGA ISRDDSKNTLYLQMNSLKTGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGT EDTAVYFCTTDRTGYSISWGGGACAACAGACTACGCTGCACCCGTGAAAGGCA SSYYYYYGMDVWGQGTTGATTCACCATCTCAAGAGATGATTCAAAAAACAC VTVSSASTKGPSVFPLAPSGCTGTATCTGCAAATGAACAGCCTGAAAACCGAG SKSTSGGTAALGCLVKDYGACACAGCCGTGTATTTCTGTACCACAGATCGGA FPEPVTVSWNSGALTSGVCCGGGTATAGCATCAGCTGGTCTAGTTACTACTAC HTFPAVLQSSGLYSLESVVTACTACGGTATGGACGTCTGGGGCCAAGGAACAA TVPSSSLGTQTYICNVNHKCAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCC PSNTKVDKKVEPKSCDKTATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA HTCPPCPAPELLGGPSVFLCCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT FPPKPKDTLMISRTPEVTCCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG VVVDVSHEDPEVKFNWYTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA VDGVEVHNAKTKPCEEQYCCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC GSTYRCVSVLTVLHQDWLTCCCTCGAGAGCGTGGTGACCGTGCCCTCCAGCA NGKEYKCKVSNKALPAPIGCTTGGGCACCCAGACCTACATCTGCAACGTGAA EKTISKAKGQPREPQVYTLTCACAAGCCCAGCAACACCAAGGTGGACAAGAA PPSRKEMTKNQVSLTCLVAGTTGAGCCCAAATCTTGTGACAAAACTCACACA KGFYPSDIAVEWESNGQPETGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG NNYKTTPPVLKSDGSFFLYGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG SKLTVDKSRWQQGNVFSCGACACCCTCATGATCTCCCGGACCCCTGAGGTCA SVMHEALHNHYTQKSLSLCATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SPGK (SEQ ID NO: 296)TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CTCCCTGTCTCCGGGTAAA (SEQ ID NO: 318)50C HC-103 EVQLVESGGGLVKPGGSL GAGGTACAGCTGGTGGAGTCTGGGGGAGGCTTGGRLSCAASGFTFGNAWMS TAAAGCCTGGGGGGTCCCTCAGACTCTCCTGTGC WVRQAPGKGLEWVGR1KSAGCCTCTGGATTCACTTTCGGTAACGCCTGGATGA KTDGGTTDYAAPVKGRFTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGA ISRDDSKNTLYLQMNSLKTGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGT EDTAVYFCTTDRTGYSISWGGGACAACAGACTACGCTGCACCCGTGAAAGGCA SSYYYYYGMDVWGQGTTGATTCACCATCTCAAGAGATGATTCAAAAAACAC VTVSSASTKGPSVFPLAPSGCTGTATCTGCAAATGAACAGCCTGAAAACCGAG SKSTSGGTAALGCLVKDYGACACAGCCGTGTATTTCTGTACCACAGATCGGA FPEPVTVSWNSGALTSGVCCGGGTATAGCATCAGCTGGTCTAGTTACTACTAC HTFPAVLQSSGLYSLESVVTACTACGGTATGGACGTCTGGGGCCAAGGAACAA TVPSSSLGTQTYICNVNHKCAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCC PSNTKVDKKVEPKSCDKTATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA HTCPPCPAPELLGGPSVFLCCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT FPPKPKDTLMISRTPEVTCCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG VVVDVSHEDPEVKFNWYTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA VDGVEVHNAKTKPCEEQYCCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC GSTYRCVSVLTVLHQDWLTCCCTCGAGAGCGTGGTGACCGTGCCCTCCAGCA NGKEYKCKVSNKALPAPIGCTTGGGCACCCAGACCTACATCTGCAACGTGAA EKTISKAKGQPREPQVYTLTCACAAGCCCAGCAACACCAAGGTGGACAAGAA PPSRKKMTKNQVSLTCLVAGTTGAGCCCAAATCTTGTGACAAAACTCACACA KGFYPSDIAVEWESNGQPETGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG NNYKTTPPVLKSDGSFFLYGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG SKLTVDKSRWQQGNVFSCGACACCCTCATGATCTCCCGGACCCCTGAGGTCA SVMHEALHNHYTQKSLSLCATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SPGK (SEQ ID NO: 297)TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGAAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CTCCCTGTCTCCGGGTAAA (SEQ ID NO: 319)50D HC-104 EVQLVESGGGLVKPGGSL GAGGTACAGCTGGTGGAGTCTGGGGGAGGCTTGGRLSCAASGFTFGNAWMS TAAAGCCTGGGGGGTCCCTCAGACTCTCCTGTGC WVRQAPGKGLEWVGR1KSAGCCTCTGGATTCACTTTCGGTAACGCCTGGATGA KTDGGTTDYAAPVKGRFTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGA ISRDDSKNTLYLQMNSLKTGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGT EDTAVYFCTTDRTGYSISWGGGACAACAGACTACGCTGCACCCGTGAAAGGCA SSYYYYYGMDVWGQGTTGATTCACCATCTCAAGAGATGATTCAAAAAACAC VTVSSASTKGPSVFPLAPCGCTGTATCTGCAAATGAACAGCCTGAAAACCGAG SRSTSESTAALGCLVKDYFGACACAGCCGTGTATTTCTGTACCACAGATCGGA PEPVTVSWNSGALTSGVHCCGGGTATAGCATCAGCTGGTCTAGTTACTACTAC TFPAVLQSSGLYSLESVVTTACTACGGTATGGACGTCTGGGGCCAAGGAACAA VPSSNFGTQTYTCNVDHKCAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCC PSNTKVDKTVERKCCVECATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCA PPCPAPPVAGPSVFLFPPKPCCTCCGAGAGCACAGCGGCCCTGGGCTGCCTGGT KDTLMISRTPEVTCVVVDCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG VSHEDPEVQFNWYVDGVETGGAACTCAGGCGCTCTGACCAGCGGCGTGCACA VHNAKTKPREEQFNSTFRCCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTAC VVSVLTVVHQDWLNGKETCCCTGGAGAGCGTGGTGACCGTGCCCTCCAGCA YKCKVSNKGLPAPIEKTIS ACTTCGGCACCCAGACCTACACCTGCAACGTAGA KTKGQPREPQVYTLPPSRK TCACAAGCCCAGCAACACCAAGGTGGACAAGAC KMTKNQVSLTCLVKGFYPAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCG SDIAVEWESNGQPENNYKTGCCCAGCACCACCTGTGGCAGGACCGTCAGTCT TTPPMLKSDGSFFLYSKLT TCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG VDKSRWQQGNVFSCSVMATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG HEALHNHYTQKSLSLSPG TGGACGTGAGCCACGAAGACCCCGAGGTCCAGTT K (SEQ ID NO: 298)CAACTGGTACGTGGACGGCGTGGAGGTGCATAAT GCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTGT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCC ATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATC CCGGAAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGAC ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGA AGTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAA (SEQ ID NO: 320) 51A HC-105EVQLVESGGGLVKPGGSL GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGG RLSCAASGFTFSNAWMSWTAAAGCCTGGGGGGTCCCTTAGACTCTCCTGTGC VRQAPGKGLEWVGRIKSKAGCCTCTGGATTCACTTTCAGTAACGCCTGGATGA TDGGTTDYTAPVKGRFTISGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGA RDDSKNTLYLQMNSLKAEGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGT DTAVYYCTTDRTGYSISWGGGACAACAGACTACACTGCACCCGTGAAAGGCA SSYYYYYGMDVWGQGTTGATTCACCATCTCAAGAGATGATTCAAAAAACAC VTVSSASTKGPSVFPLAPSGCTGTATCTGCAAATGAATAGCCTGAAAGCCGAG SKSTSGGTAALGCLVKDYGACACAGCCGTGTATTACTGTACCACAGATCGGA FPEPVTVSWNSGALTSGVCCGGGTATAGCATCAGCTGGTCTAGTTACTACTAC HTFPAVLQSSGLYSLESVVTACTACGGTATGGACGTCTGGGGCCAAGGGACAA TVPSSSLGTQTYICNVNHKCAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCC PSNTKVDKKVEPKSCDKTATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA HTCPPCPAPELLGGPSVFLCCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT FPPKPKDTLMISRTPEVTCCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG VVVDVSHEDPEVKFNWYTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA VDGVEVHNAKTKPCEEQYCCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC GSTYRCVSVLTVLHQDWLTCCCTCGAGAGCGTGGTGACCGTGCCCTCCAGCA NGKEYKCKVSNKALPAPIGCTTGGGCACCCAGACCTACATCTGCAACGTGAA EKTISKAKGQPREPQVYTL TCACAAGCCCAGCAACACCAAGGTGGACAAGAA PPSRKEMTKNQVSLTCLV AGTTGAGCCCAAATCTTGTGACAAAACTCACACA KGFYPSDIAVEWESNGQPE TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG NNYKTTPPVLKSDGSFFLY GACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG SKLTVDKSRWQQGNVFSCGACACCCTCATGATCTCCCGGACCCCTGAGGTCA SVMHEALHNHYTQKSLSL CATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SPGK (SEQ ID NO: 299)TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CTCCCTGTCTCCGGGTAAA (SEQ ID NO: 321)51B HC-106 EVQLVESGGGLVKPGGSL GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGRLSCAASGFTFSNAWMSW TAAAGCCTGGGGGGTCCCTTAGACTCTCCTGTGC VRQAPGKELEWVGRIKSKAGCCTCTGGATTCACTTTCAGTAACGCCTGGATGA TDGGTTDYTAPVKGRFTISGCTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGA RDDSKNTLYLQMNSLKAEGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGT DTAVYYCTTDRTGYSISWGGGACAACAGACTACACTGCACCCGTGAAAGGCA SSYYYYYGMDVWGQGTTGATTCACCATCTCAAGAGATGATTCAAAAAACAC VTVSSASTKGPSVFPLAPSGCTGTATCTGCAAATGAATAGCCTGAAAGCCGAG SKSTSGGTAALGCLVKDYGACACAGCCGTGTATTACTGTACCACAGATCGGA FPEPVTVSWNSGALTSGVCCGGGTATAGCATCAGCTGGTCTAGTTACTACTAC HTFPAVLQSSGLYSLESVVTACTACGGTATGGACGTCTGGGGCCAAGGAACAA TVPSSSLGTQTYICNVNHKCAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCC PSNTKVDKKVEPKSCDKTATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA HTCPPCPAPELLGGPSVFLCCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT FPPKPKDTLMISRTPEVTCCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG VVVDVSHEDPEVKFNWYTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA VDGVEVHNAKTKPCEEQYCCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC GSTYRCVSVLTVLHQDWLTCCCTCGAGAGCGTGGTGACCGTGCCCTCCAGCA NGKEYKCKVSNKALPAPIGCTTGGGCACCCAGACCTACATCTGCAACGTGAA EKTISKAKGQPREPQVYTL TCACAAGCCCAGCAACACCAAGGTGGACAAGAA PPSRKEMTKNQVSLTCLV AGTTGAGCCCAAATCTTGTGACAAAACTCACACA KGFYPSDIAVEWESNGQPE TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG NNYKTTPPVLKSDGSFFLY GACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG SKLTVDKSRWQQGNVFSCGACACCCTCATGATCTCCCGGACCCCTGAGGTCA SVMHEALHNHYTQKSLSLCATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SPGK (SEQ ID NO: 300)TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CTCCCTGTCTCCGGGTAAA (SEQ ID NO: 322)51C HC-107 EVQLVESGGGLVKPGGSL GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGRLSCAASGFTFSNAWMSW TAAAGCCTGGGGGGTCCCTTAGACTCTCCTGTGC VRQAPGKGLEWVGRIKSKAGCCTCTGGATTCACTTTCAGTAACGCCTGGATGA TDGGTTDYTAPVKGRFTISGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGA RDDSKNTLYLQMNSLKAEGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGT DTAVYYCTTDRTGYSISWGGGACAACAGACTACACTGCACCCGTGAAAGGCA SSYYYYYGMDVWGQGTTGATTCACCATCTCAAGAGATGATTCAAAAAACAC VTVSSASTKGPSVFPLAPSGCTGTATCTGCAAATGAATAGCCTGAAAGCCGAG SKSTSGGTAALGCLVKDYGACACAGCCGTGTATTACTGTACCACAGATCGGA FPEPVTVSWNSGALTSGVCCGGGTATAGCATCAGCTGGTCTAGTTACTACTAC HTFPAVLQSSGLYSLESVVTACTACGGTATGGACGTCTGGGGCCAAGGGACAA TVPSSSLGTQTYICNVNHKCAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCC PSNTKVDKKVEPKSCDKTATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA HTCPPCPAPELLGGPSVFLCCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT FPPKPKDTLMISRTPEVTCCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG VVVDVSHEDPEVKFNWYTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA VDGVEVHNAKTKPCEEQYCCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC GSTYRCVSVLTVLHQDWLTCCCTCGAGAGCGTGGTGACCGTGCCCTCCAGCA NGKEYKCKVSNKALPAPIGCTTGGGCACCCAGACCTACATCTGCAACGTGAA EKTISKAKGQPREPQVYTLTCACAAGCCCAGCAACACCAAGGTGGACAAGAA PPSRKKMTKNQVSLTCLVAGTTGAGCCCAAATCTTGTGACAAAACTCACACA KGFYPSDIAVEWESNGQPETGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG NNYKTTPPVLKSDGSFFLYGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG SKLTVDKSRWQQGNVFSCGACACCCTCATGATCTCCCGGACCCCTGAGGTCA SVMHEALHNHYTQKSLSLCATGCGTGGTGGTGGACGTGAGCCACGAAGACCC SPGK (SEQ ID NO: 301)TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGAAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CTCCCTGTCTCCGGGTAAA (SEQ ID NO: 323)51D HC-108 EVQLVESGGGLVKPGGSL GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGRLSCAASGFTFSNAWMSW TAAAGCCTGGGGGGTCCCTTAGACTCTCCTGTGC VRQAPGKGLEWVGRIKSKAGCCTCTGGATTCACTTTCAGTAACGCCTGGATGA TDGGTTDYTAPVKGRFTISGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGA RDDSKNTLYLQMNSLKAEGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGT DTAVYYCTTDRTGYSISWGGGACAACAGACTACACTGCACCCGTGAAAGGCA SSYYYYYGMDVWGQGTTGATTCACCATCTCAAGAGATGATTCAAAAAACAC VTVSSASTKGPSVFPLAPCGCTGTATCTGCAAATGAATAGCCTGAAAGCCGAG SRSTSESTAALGCLVKDYFGACACAGCCGTGTATTACTGTACCACAGATCGGA PEPVTVSWNSGALTSGVHCCGGGTATAGCATCAGCTGGTCTAGTTACTACTAC TFPAVLQSSGLYSLESVVTTACTACGGTATGGACGTCTGGGGCCAAGGAACAA VPSSNFGTQTYTCNVDHKCAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCC PSNTKVDKTVERKCCVECATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCA PPCPAPPVAGPSVFLFPPKPCCTCCGAGAGCACAGCGGCCCTGGGCTGCCTGGT KDTLMISRTPEVTCVVVDCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG VSHEDPEVQFNWYVDGVETGGAACTCAGGCGCTCTGACCAGCGGCGTGCACA VHNAKTKPREEQFNSTFRCCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTAC VVSVLTVVHQDWLNGKETCCCTGGAGAGCGTGGTGACCGTGCCCTCCAGCA YKCKVSNKGLPAPIEKTISACTTCGGCACCCAGACCTACACCTGCAACGTAGA KTKGQPREPQVYTLPPSRKTCACAAGCCCAGCAACACCAAGGTGGACAAGAC KMTKNQVSLTCLVKGFYPAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCG SDIAVEWESNGQPENNYKTGCCCAGCACCACCTGTGGCAGGACCGTCAGTCT TTPPMLKSDGSFFLYSKLTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG VDKSRWQQGNVFSCSVMATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG HEALHNHYTQKSLSLSPGTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTT K (SEQ ID NO: 302)CAACTGGTACGTGGACGGCGTGGAGGTGCATAAT GCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTGT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCC ATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATC CCGGAAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGAC ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGA AGTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAA (SEQ ID NO: 324) 52A, 54A,HC-109 QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG 55ARLSCAASGFTFSSFGMHW TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVISFDAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GSIKYSVDSVKGRFTISRDACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA NSKNTLFLQMNSLRAEDTGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AVYYCARDRLNYYDSSGYAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA YHYKYYGMAVWGQGTTCCATCTCCAGAGACAATTCAAAGAACACGCTGTT VTVSSASTKGPSVFPLAPSTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG SKSTSGGTAALGCLVKDYGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT FPEPVTVSWNSGALTSGVACTATGATAGTAGTGGTTATTATCACTACAAATAC HTFPAVLQSSGLYSLESVVTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG TVPSSSLGTQTYICNVNHKTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG PSNTKVDKKVEPKSCDKTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC HTCPPCPAPELLGGPSVFLTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG FPPKPKDTLMISRTPEVTCGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA VVVDVSHEDPEVKFNWYACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT VDGVEVHNAKTKPCEEQYCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC GSTYRCVSVLTVLHQDWLTCGAGAGCGTGGTGACCGTGCCCTCCAGCAGCTT NGKEYKCKVSNKALPAPIGGGCACCCAGACCTACATCTGCAACGTGAATCAC EKTISKAKGQPREPQVYTLAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT PPSRKEMTKNQVSLTCLVGAGCCCAAATCTTGTGACAAAACTCACACATGCC KGFYPSDIAVEWESNGQPECACCGTGCCCAGCACCTGAACTCCTGGGGGGACC NNYKTTPPVLKSDGSFFLYGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA SKLTVDKSRWQQGNVFSCCCCTCATGATCTCCCGGACCCCTGAGGTCACATGC SVMHEALHNHYTQKSLSLGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG SPGK (SEQ ID NO: 303)TAAAGTTCAACTGGTACGTGGACGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC CCCCATCCCGGAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCC TGTCTCCGGGTAAA (SEQ ID NO: 325)52B, 54B, HC-110 QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG55B RLSCAASGFTFSSFGMHW TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCVRQAPGKELEWVAVISFD AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCGSIKYSVDSVKGRFTISRD ACTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGANSKNTLFLQMNSLRAEDT GTGGGTGGCAGTTATATCATTTGATGGAAGTATT AVYYCARDRLNYYDSSGYAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA YHYKYYGMAVWGQGTTCCATCTCCAGAGACAATTCAAAGAACACGCTGTT VTVSSASTKGPSVFPLAPSTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG SKSTSGGTAALGCLVKDYGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT FPEPVTVSWNSGALTSGVACTATGATAGTAGTGGTTATTATCACTACAAATAC HTFPAVLQSSGLYSLESVVTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG TVPSSSLGTQTYICNVNHKTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG PSNTKVDKKVEPKSCDKTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC HTCPPCPAPELLGGPSVFLTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG FPPKPKDTLMISRTPEVTCGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA VVVDVSHEDPEVKFNWYACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT VDGVEVHNAKTKPCEEQYCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC GSTYRCVSVLTVLHQDWLTCGAGAGCGTGGTGACCGTGCCCTCCAGCAGCTT NGKEYKCKVSNKALPAPIGGGCACCCAGACCTACATCTGCAACGTGAATCAC EKTISKAKGQPREPQVYTL AAGCCCAGCAACACCAAGGTGGACAAGAAAGTT PPSRKEMTKNQVSLTCLV GAGCCCAAATCTTGTGACAAAACTCACACATGCC KGFYPSDIAVEWESNGQPE CACCGTGCCCAGCACCTGAACTCCTGGGGGGACC NNYKTTPPVLKSDGSFFLY GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA SKLTVDKSRWQQGNVFSCCCCTCATGATCTCCCGGACCCCTGAGGTCACATGC SVMHEALHNHYTQKSLSLGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG SPGK (SEQ ID NO: 304)TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC CCCCATCCCGGAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCC TGTCTCCGGGTAAA (SEQ ID NO: 326)52C, 54C, HC-111 QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG55C RLSCAASGFTFSSFGMHW TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCVRQAPGKGLEWVAVISFD AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCGSIKYSVDSVKGRFTISRD ACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGANSKNTLFLQMNSLRAEDT GTGGGTGGCAGTTATATCATTTGATGGAAGTATT AVYYCARDRLNYYDSSGYAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA YHYKYYGMAVWGQGTTCCATCTCCAGAGACAATTCAAAGAACACGCTGTT VTVSSASTKGPSVFPLAPSTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG SKSTSGGTAALGCLVKDYGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT FPEPVTVSWNSGALTSGVACTATGATAGTAGTGGTTATTATCACTACAAATAC HTFPAVLQSSGLYSLESVVTACGGTATGGCCGTCTGGGGCCAAGGAACAACAG TVPSSSLGTQTYICNVNHKTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG PSNTKVDKKVEPKSCDKTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC HTCPPCPAPELLGGPSVFLTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG FPPKPKDTLMISRTPEVTCGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA VVVDVSHEDPEVKFNWYACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT VDGVEVHNAKTKPCEEQYCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC GSTYRCVSVLTVLHQDWLTCGAGAGCGTGGTGACCGTGCCCTCCAGCAGCTT NGKEYKCKVSNKALPAPIGGGCACCCAGACCTACATCTGCAACGTGAATCAC EKTISKAKGQPREPQVYTLAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT PPSRKKMTKNQVSLTCLVGAGCCCAAATCTTGTGACAAAACTCACACATGCC KGFYPSDIAVEWESNGQPECACCGTGCCCAGCACCTGAACTCCTGGGGGGACC NNYKTTPPVLKSDGSFFLYGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA SKLTVDKSRWQQGNVFSCCCCTCATGATCTCCCGGACCCCTGAGGTCACATGC SVMHEALHNHYTQKSLSLGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG SPGK (SEQ ID NO: 305)TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC CCCCATCCCGGAAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCC TGTCTCCGGGTAAA (SEQ ID NO: 327) 52DHC-112 QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGRLSCAASGFTFSSFGMHW TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVISFDAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GSIKYSVDSVKGRFTISRD ACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA NSKNTLFLQMNSLRAEDTGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AVYYCARDRLNYYDSSGYAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA YHYKYYGMAVWGQGTTCCATCTCCAGAGACAATTCAAAGAACACGCTGTT VTVSSASTKGPSVFPLAPCTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG SRSTSESTAALGCLVKDYFGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT PEPVTVSWNSGALTSGVHACTATGATAGTAGTGGTTATTATCACTACAAATAC TFPAVLQSSGLYSLESVVTTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG VPSSNFGTQTYTCNVDHKTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG PSNTKVDKTVERKCCVECGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTC PPCPAPPVAGPSVFLFPPKPCGAGAGCACAGCGGCCCTGGGCTGCCTGGTCAAG KDTLMISRTPEVTCVVVDGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA VSHEDPEVQFNWYVDGVEACTCAGGCGCTCTGACCAGCGGCGTGCACACCTT VHNAKTKPREEQFNSTFRCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCC VVSVLTVVHQDWLNGKETGGAGAGCGTGGTGACCGTGCCCTCCAGCAACTT YKCKVSNKGLPAPIEKTIS CGGCACCCAGACCTACACCTGCAACGTAGATCAC KTKGQPREPQVYTLPPSRK AAGCCCAGCAACACCAAGGTGGACAAGACAGTT KMTKNQVSLTCLVKGFYPGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCC SDIAVEWESNGQPENNYKCAGCACCACCTGTGGCAGGACCGTCAGTCTTCCT TTPPMLKSDGSFFLYSKLTCTTCCCCCCAAAACCCAAGGACACCCTCATGATC VDKSRWQQGNVFSCSVMTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGG HEALHNHYTQKSLSLSPGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAA K (SEQ ID NO: 306)CTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTGTGCA CCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCCATCG AGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGG AAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGC CGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGAAGTCC GACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTT CTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA (SEQ ID NO: 328) 53A, 56AHC-113 QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGRLSCAASGFTFSSFGMHW TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVISFDAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GSIKYSVDSVKGRFTISRDACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA NSKNTLFLQMNSLRAEDTGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AVYYCARDRLNYYESSGYAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA YHYKYYGMAVWGQGTTCCATCTCCAGAGACAATTCAAAGAACACGCTGTT VTVSSASTKGPSVFPLAPSTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG SKSTSGGTAALGCLVKDYGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT FPEPVTVSWNSGALTSGVACTATGAGAGTAGTGGTTATTATCACTACAAATA HTFPAVLQSSGLYSLESVVCTACGGTATGGCCGTCTGGGGCCAAGGGACAACA TVPSSSLGTQTYICNVNHKGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATC PSNTKVDKKVEPKSCDKTGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT HTCPPCPAPELLGGPSVFLCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA FPPKPKDTLMISRTPEVTCGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG VVVDVSHEDPEVKFNWYAACTCAGGCGCCCTGACCAGCGGCGTGCACACCT VDGVEVHNAKTKPCEEQYTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC GSTYRCVSVLTVLHQDWLCTCGAGAGCGTGGTGACCGTGCCCTCCAGCAGCT NGKEYKCKVSNKALPAPITGGGCACCCAGACCTACATCTGCAACGTGAATCA EKTISKAKGQPREPQVYTLCAAGCCCAGCAACACCAAGGTGGACAAGAAAGT PPSRKEMTKNQVSLTCLVTGAGCCCAAATCTTGTGACAAAACTCACACATGC KGFYPSDIAVEWESNGQPECCACCGTGCCCAGCACCTGAACTCCTGGGGGGAC NNYKTTPPVLKSDGSFFLYCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC SKLTVDKSRWQQGNVFSCACCCTCATGATCTCCCGGACCCCTGAGGTCACAT SVMHEALHNHYTQKSLSLGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA SPGK (SEQ ID NO: 307)GGTAAAGTTCAACTGGTACGTGGACGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCC CAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTG CCCCCATCCCGGAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCC AGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 329)53B, 56B HC-114 QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGRLSCAASGFTFSSFGMHW TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKELEWVAVISFDAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GSIKYSVDSVKGRFTISRDACTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGA NSKNTLFLQMNSLRAEDTGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AVYYCARDRLNYYESSGYAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA YHYKYYGMAVWGQGTTCCATCTCCAGAGACAATTCAAAGAACACGCTGTT VTVSSASTKGPSVFPLAPSTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG SKSTSGGTAALGCLVKDYGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT FPEPVTVSWNSGALTSGVACTATGAGAGTAGTGGTTATTATCACTACAAATA HTFPAVLQSSGLYSLESVVCTACGGTATGGCCGTCTGGGGCCAAGGGACAACA TVPSSSLGTQTYICNVNHKGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATC PSNTKVDKKVEPKSCDKTGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT HTCPPCPAPELLGGPSVFLCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA FPPKPKDTLMISRTPEVTCGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG VVVDVSHEDPEVKFNWYAACTCAGGCGCCCTGACCAGCGGCGTGCACACCT VDGVEVHNAKTKPCEEQYTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC GSTYRCVSVLTVLHQDWLCTCGAGAGCGTGGTGACCGTGCCCTCCAGCAGCT NGKEYKCKVSNKALPAPITGGGCACCCAGACCTACATCTGCAACGTGAATCA EKTISKAKGQPREPQVYTL CAAGCCCAGCAACACCAAGGTGGACAAGAAAGT PPSRKEMTKNQVSLTCLV TGAGCCCAAATCTTGTGACAAAACTCACACATGC KGFYPSDIAVEWESNGQPE CCACCGTGCCCAGCACCTGAACTCCTGGGGGGAC NNYKTTPPVLKSDGSFFLY CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC SKLTVDKSRWQQGNVFSCACCCTCATGATCTCCCGGACCCCTGAGGTCACAT SVMHEALHNHYTQKSLSLGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA SPGK (SEQ ID NO: 308)GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCC CAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTG CCCCCATCCCGGAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCC AGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 330)53C, 56C HC-115 QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGRLSCAASGFTFSSFGMHW TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVISFDAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GSIKYSVDSVKGRFTISRDACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA NSKNTLFLQMNSLRAEDTGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AVYYCARDRLNYYESSGYAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA YHYKYYGMAVWGQGTTCCATCTCCAGAGACAATTCAAAGAACACGCTGTT VTVSSASTKGPSVFPLAPSTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG SKSTSGGTAALGCLVKDYGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT FPEPVTVSWNSGALTSGVACTATGAGAGTAGTGGTTATTATCACTACAAATA HTFPAVLQSSGLYSLESVVCTACGGTATGGCCGTCTGGGGCCAAGGAACAACA TVPSSSLGTQTYICNVNHKGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATC PSNTKVDKKVEPKSCDKTGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT HTCPPCPAPELLGGPSVFLCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA FPPKPKDTLMISRTPEVTCGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG VVVDVSHEDPEVKFNWYAACTCAGGCGCCCTGACCAGCGGCGTGCACACCT VDGVEVHNAKTKPCEEQYTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC GSTYRCVSVLTVLHQDWLCTCGAGAGCGTGGTGACCGTGCCCTCCAGCAGCT NGKEYKCKVSNKALPAPITGGGCACCCAGACCTACATCTGCAACGTGAATCA EKTISKAKGQPREPQVYTLCAAGCCCAGCAACACCAAGGTGGACAAGAAAGT PPSRKKMTKNQVSLTCLVTGAGCCCAAATCTTGTGACAAAACTCACACATGC KGFYPSDIAVEWESNGQPECCACCGTGCCCAGCACCTGAACTCCTGGGGGGAC NNYKTTPPVLKSDGSFFLYCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC SKLTVDKSRWQQGNVFSCACCCTCATGATCTCCCGGACCCCTGAGGTCACAT SVMHEALHNHYTQKSLSLGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA SPGK (SEQ ID NO: 309)GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCC CAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTG CCCCCATCCCGGAAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCC AGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGAAGTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 331) 57AHC-116 QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGRLSCAASGFTFSSYGMHW TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVIWYAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGC DGSNKYYADSVKGRFIISRACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA DKSKNTLYLQMNSLRAEDGTGGGTGGCAGTTATATGGTATGATGGAAGTAAT TAVYYCARAGGIAAAGLYAAATACTATGCAGACTCCGTGAAGGGCCGATTCA YYYGMDVWGQGTTVTVSTCATCTCCAGAGATAAATCCAAGAACACGCTGTA SASTKGPSVFPLAPSSKSTSTCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GGTAALGCLVKDYFPEPVGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAG TVSWNSGALTSGVHTFPACAGCAGCTGGCCTCTACTACTACTACGGTATGGA VLQSSGLYSLESVVTVPSSCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCT SLGTQTYICNVNHKPSNTKAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT VDKKVEPKSCDKTHTCPPGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA CPAPELLGGPSVFLFPPKPGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC KDTLMISRTPEVTCVVVDCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC VSHEDPEVKFNWYVDGVECCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC VHNAKTKPCEEQYGSTYRCTACAGTCCTCAGGACTCTACTCCCTCGAGAGCGT CVSVLTVLHQDWLNGKEGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG YKCKVSNKALPAPIEKTISACCTACATCTGCAACGTGAATCACAAGCCCAGCA KAKGQPREPQVYTLPPSRACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC KEMTKNQVSLTCLVKGFYTTGTGACAAAACTCACACATGCCCACCGTGCCCA PSDIAVEWESNGQPENNYGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC KTTPPVLKSDGSFFLYSKL TCTTCCCCCCAAAACCCAAGGACACCCTCATGAT TVDKSRWQQGNVFSCSVCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTG MHEALHNHYTQKSLSLSPGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA GK (SEQ ID NO: 310)ACTGGTACGTGGACGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGAAGT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAA (SEQ ID NO: 332) 57B HC-117QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGG RLSCAASGFTFSSYGMHWTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKELEWVAVIWYAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGC DGSNKYYADSVKGRFIISRACTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGA DKSKNTLYLQMNSLRAEDGTGGGTGGCAGTTATATGGTATGATGGAAGTAAT TAVYYCARAGGIAAAGLYAAATACTATGCAGACTCCGTGAAGGGCCGATTCA YYYGMDVWGQGTTVTVSTCATCTCCAGAGATAAATCCAAGAACACGCTGTA SASTKGPSVFPLAPSSKSTSTCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GGTAALGCLVKDYFPEPVGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAG TVSWNSGALTSGVHTFPACAGCAGCTGGCCTCTACTACTACTACGGTATGGA VLQSSGLYSLESVVTVPSSCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCT SLGTQTYICNVNHKPSNTKAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT VDKKVEPKSCDKTHTCPPGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA CPAPELLGGPSVFLFPPKPGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC KDTLMISRTPEVTCVVVDCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC VSHEDPEVKFNWYVDGVECCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC VHNAKTKPCEEQYGSTYRCTACAGTCCTCAGGACTCTACTCCCTCGAGAGCGT CVSVLTVLHQDWLNGKEGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG YKCKVSNKALPAPIEKTISACCTACATCTGCAACGTGAATCACAAGCCCAGCA KAKGQPREPQVYTLPPSRACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC KEMTKNQVSLTCLVKGFYTTGTGACAAAACTCACACATGCCCACCGTGCCCA PSDIAVEWESNGQPENNYGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC KTTPPVLKSDGSFFLYSKLTCTTCCCCCCAAAACCCAAGGACACCCTCATGAT TVDKSRWQQGNVFSCSVCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTG MHEALHNHYTQKSLSLSPGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA GK (SEQ ID NO: 311)ACTGGTACGTGGACGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGAAGT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAA (SEQ ID NO: 333) 57C HC-118QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGG RLSCAASGFTFSSYGMHWTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVIWYAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGC DGSNKYYADSVKGRFIISRACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA DKSKNTLYLQMNSLRAEDGTGGGTGGCAGTTATATGGTATGATGGAAGTAAT TAVYYCARAGGIAAAGLYAAATACTATGCAGACTCCGTGAAGGGCCGATTCA YYYGMDVWGQGTTVTVSTCATCTCCAGAGATAAATCCAAGAACACGCTGTA SASTKGPSVFPLAPSSKSTSTCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GGTAALGCLVKDYFPEPVGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAG TVSWNSGALTSGVHTFPACAGCAGCTGGCCTCTACTACTACTACGGTATGGA VLQSSGLYSLESVVTVPSSCGTCTGGGGCCAAGGAACAACAGTTACCGTCTCT SLGTQTYICNVNHKPSNTKAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT VDKKVEPKSCDKTHTCPPGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA CPAPELLGGPSVFLFPPKPGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC KDTLMISRTPEVTCVVVDCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC VSHEDPEVKFNWYVDGVECCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC VHNAKTKPCEEQYGSTYRCTACAGTCCTCAGGACTCTACTCCCTCGAGAGCGT CVSVLTVLHQDWLNGKEGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG YKCKVSNKALPAPIEKTISACCTACATCTGCAACGTGAATCACAAGCCCAGCA KAKGQPREPQVYTLPPSRACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC KKMTKNQVSLTCLVKGFYTTGTGACAAAACTCACACATGCCCACCGTGCCCA PSDIAVEWESNGQPENNYGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC KTTPPVLKSDGSFFLYSKLTCTTCCCCCCAAAACCCAAGGACACCCTCATGAT TVDKSRWQQGNVFSCSVCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTT MHEALHNHYTQKSLSL SPGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA GK (SEQ ID NO: 312)ACTGGTACGTGGACGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GAAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGAAGT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAA (SEQ ID NO: 334) 57D HC-119QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGG RLSCAASGFTFSSYGMHWTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVIWYAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGC DGSNKYYADSVKGRFIISRACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA DKSKNTLYLQMNSLRAEDGTGGGTGGCAGTTATATGGTATGATGGAAGTAAT TAVYYCARAGGIAAAGLYAAATACTATGCAGACTCCGTGAAGGGCCGATTCA YYYGMDVWGQGTTVTVSTCATCTCCAGAGATAAATCCAAGAACACGCTGTA SASTKGPSVFPLAPCSRSTSTCTGCAAATGAACAGCCTGAGAGCCGAGGACACG ESTAALGCLVKDYFPEPVTGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAG VSWNSGALTSGVHTFPAVCAGCAGCTGGCCTCTACTACTACTACGGTATGGA LQSSGLYSLESVVTVPSSNCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCT FGTQTYTCNVDHKPSNTKAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT VDKTVERKCCVECPPCPAGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACA PPVAGPSVFLFPPKPKDTLCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC MISRTPEVTCVVVDVSHECCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC DPEVQFNWYVDGVEVHNTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCC AKTKPREEQFNSTFRVVSV TACAGTCCTCAGGACTCTACTCCCTGGAGAGCGT LTVVHQDWLNGKEYKCKGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAG VSNKGLPAPIEKTISKTKG ACCTACACCTGCAACGTAGATCACAAGCCCAGCA QPREPQVYTLPPSRKKMTACACCAAGGTGGACAAGACAGTTGAGCGCAAAT KNQVSLTCLVKGFYPSDIA GTTGTGTCGAGTGCCCACCGTGCCCAGCACCACC VEWESNGQPENNYKTTPPTGTGGCAGGACCGTCAGTCTTCCTCTTCCCCCCAA MLKSDGSFFLYSKLTVDKAACCCAAGGACACCCTCATGATCTCCCGGACCCC SRWQQGNVFSCSVMHEALTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAC HNHYTQKSLSLSPGK (SEQGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGG ID NO: 313)ACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC ACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTGTGCACCAGGACTGGC TGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCCATCGAGAAAACCATC TCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGAAGAAGATGA CCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGAAGTCCGACGGCTCCTT CTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCG TGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 335) 58A HC-120QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGG RLSCAASGFTFSSYGMHWTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVIWYAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGC DGSNKYYAESVKGRFIISRACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA DKSKNTLYLQMNSLRAEDGTGGGTGGCAGTTATATGGTATGATGGAAGTAAT TAVYYCARAGGIAAAGLYAAATACTATGCAGAGTCCGTGAAGGGCCGATTCA YYYGMDVWGQGTTVTVSTCATCTCCAGAGATAAATCCAAGAACACGCTGTA SASTKGPSVFPLAPSSKSTSTCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GGTAALGCLVKDYFPEPVGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAG TVSWNSGALTSGVHTFPACAGCAGCTGGCCTCTACTACTACTACGGTATGGA VLQSSGLYSLESVVTVPSSCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCT SLGTQTYICNVNHKPSNTKAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT VDKKVEPKSCDKTHTCPPGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA CPAPELLGGPSVFLFPPKPGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC KDTLMISRTPEVTCVVVDCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC VSHEDPEVKFNWYVDGVECCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC VHNAKTKPCEEQYGSTYRCTACAGTCCTCAGGACTCTACTCCCTCGAGAGCGT CVSVLTVLHQDWLNGKEGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG YKCKVSNKALPAPIEKTISACCTACATCTGCAACGTGAATCACAAGCCCAGCA KAKGQPREPQVYTLPPSRACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC KEMTKNQVSLTCLVKGFYTTGTGACAAAACTCACACATGCCCACCGTGCCCA PSDIAVEWESNGQPENNYGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC KTTPPVLKSDGSFFLYSKLTCTTCCCCCCAAAACCCAAGGACACCCTCATGAT TVDKSRWQQGNVFSCSVCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTG MHEALHNHYTQKSLSL SPGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA GK (SEQ ID NO: 314)ACTGGTACGTGGACGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGAAGT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAA (SEQ ID NO: 336) 58B HC-121QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGG RLSCAASGFTFSSYGMHWTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKELEWVAVIWYAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGC DGSNKYYAESVKGRFIISR ACTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGA DKSKNTLYLQMNSLRAEDGTGGGTGGCAGTTATATGGTATGATGGAAGTAAT TAVYYCARAGGIAAAGLYAAATACTATGCAGAGTCCGTGAAGGGCCGATTCA YYYGMDVWGQGTTVTVSTCATCTCCAGAGATAAATCCAAGAACACGCTGTA SASTKGPSVFPLAPSSKSTSTCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GGTAALGCLVKDYFPEPVGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAG TVSWNSGALTSGVHTFPACAGCAGCTGGCCTCTACTACTACTACGGTATGGA VLQSSGLYSLESVVTVPSS CGTCTGGGGCCAAGGGACAACAGTTACCGTCTCT SLGTQTYICNVNHKPSNTK AGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT VDKKVEPKSCDKTHTCPPGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA CPAPELLGGPSVFLFPPKP GCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC KDTLMISRTPEVTCVVVDCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC VSHEDPEVKFNWYVDGVECCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC VHNAKTKPCEEQYGSTYRCTACAGTCCTCAGGACTCTACTCCCTCGAGAGCGT CVSVLTVLHQDWLNGKEGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG YKCKVSNKALPAPIEKTISACCTACATCTGCAACGTGAATCACAAGCCCAGCA KAKGQPREPQVYTLPPSRACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC KEMTKNQVSLTCLVKGFYTTGTGACAAAACTCACACATGCCCACCGTGCCCA PSDIAVEWESNGQPENNYGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC KTTPPVLKSDGSFFLYSKLTCTTCCCCCCAAAACCCAAGGACACCCTCATGAT TVDKSRWQQGNVFSCSVCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTG MHEALHNHYTQKSLSLSPGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA GK (SEQ ID NO: 315)ACTGGTACGTGGACGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GAAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGAAGT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAA (SEQ ID NO: 337) 58C HC-122QVQLVESGGGVVQPGRSL CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGG RLSCAASGFTFSSYGMHWTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC VRQAPGKGLEWVAVIWYAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGC DGSNKYYAESVKGRFIISRACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA DKSKNTLYLQMNSLRAEDGTGGGTGGCAGTTATATGGTATGATGGAAGTAAT TAVYYCARAGGIAAAGLYAAATACTATGCAGAGTCCGTGAAGGGCCGATTCA YYYGMDVWGQGTTVTVSTCATCTCCAGAGATAAATCCAAGAACACGCTGTA SASTKGPSVFPLAPSSKSTSTCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GGTAALGCLVKDYFPEPVGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAG TVSWNSGALTSGVHTFPACAGCAGCTGGCCTCTACTACTACTACGGTATGGA VLQSSGLYSLESVVTVPSSCGTCTGGGGCCAAGGAACAACAGTTACCGTCTCT SLGTQTYICNVNHKPSNTKAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT VDKKVEPKSCDKTHTCPPGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA CPAPELLGGPSVFLFPPKPGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC KDTLMISRTPEVTCVVVDCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC VSHEDPEVKFNWYVDGVECCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC VHNAKTKPCEEQYGSTYRCTACAGTCCTCAGGACTCTACTCCCTCGAGAGCGT CVSVLTVLHQDWLNGKEGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG YKCKVSNKALPAPIEKTISACCTACATCTGCAACGTGAATCACAAGCCCAGCA KAKGQPREPQVYTLPPSRACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC KKMTKNQVSLTCLVKGFYTTGTGACAAAACTCACACATGCCCACCGTGCCCA PSDIAVEWESNGQPENNYGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC KTTPPVLKSDGSFFLYSKLTCTTCCCCCCAAAACCCAAGGACACCCTCATGAT TVDKSRWQQGNVFSCSVCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTT MHEALHNHYTQKSLSL SPGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA GK (SEQ ID NO: 316)ACTGGTACGTGGACGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GAAGAAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGAAGT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAA (SEQ ID NO: 338)

In some embodiments, the heterodimeric antibody of the inventioncomprises an anti-CGRP receptor light chain from Table 7A and ananti-CGRP receptor heavy chain from Table 7B. Exemplary pairs ofanti-CGRP receptor light and heavy chains that may be incorporated intoa heterodimeric antibody include, but are not limited to: LC-101 (SEQ IDNO: 271) and HC-101 (SEQ ID NO: 295); LC-102 (SEQ ID NO: 272) and HC-102(SEQ ID NO: 296); LC-101 (SEQ ID NO: 271) and HC-103 (SEQ ID NO: 297);LC-101 (SEQ ID NO: 271) and HC-104 (SEQ ID NO: 298); LC-103 (SEQ ID NO:273) and HC-105 (SEQ ID NO: 299); LC-104 (SEQ ID NO: 274) and HC-106(SEQ ID NO: 300); LC-103 (SEQ ID NO: 273) and HC-107 (SEQ ID NO: 301);LC-103 (SEQ ID NO: 273) and HC-108 (SEQ ID NO: 302); LC-105 (SEQ ID NO:275) and HC-109 (SEQ ID NO: 303); LC-106 (SEQ ID NO: 276) and HC-110(SEQ ID NO: 304); LC-105 (SEQ ID NO: 275) and HC-111 (SEQ ID NO: 305);LC-105 (SEQ ID NO: 275) and HC-112 (SEQ ID NO: 306); LC-105 (SEQ ID NO:275) and HC-113 (SEQ ID NO: 307); LC-106 (SEQ ID NO: 276) and HC-114(SEQ ID NO: 308); LC-105 (SEQ ID NO: 275) and HC-115 (SEQ ID NO: 309);LC-107 (SEQ ID NO: 277) and HC-109 (SEQ ID NO: 303); LC-108 (SEQ ID NO:278) and HC-110 (SEQ ID NO: 304); LC-107 (SEQ ID NO: 277) and HC-111(SEQ ID NO: 305); LC-109 (SEQ ID NO: 279) and HC-109 (SEQ ID NO: 303);LC-110 (SEQ ID NO: 280) and HC-110 (SEQ ID NO: 304); LC-109 (SEQ ID NO:279) and HC-111 (SEQ ID NO: 305); LC-107 (SEQ ID NO: 277) and HC-113(SEQ ID NO: 307); LC-108 (SEQ ID NO: 278) and HC-114 (SEQ ID NO: 308);LC-107 (SEQ ID NO: 277) and HC-115 (SEQ ID NO: 309); LC-111 (SEQ ID NO:281) and HC-116 (SEQ ID NO: 310); LC-112 (SEQ ID NO: 282) and HC-117(SEQ ID NO: 311); LC-111 (SEQ ID NO: 281) and HC-118 (SEQ ID NO: 312);LC-111 (SEQ ID NO: 281) and HC-119 (SEQ ID NO: 313); LC-111 (SEQ ID NO:281) and HC-120 (SEQ ID NO: 314); LC-112 (SEQ ID NO: 282) and HC-121(SEQ ID NO: 315); and LC-111 (SEQ ID NO: 281) and HC-122 (SEQ ID NO:316).

The anti-CGRP receptor light chain and/or heavy chain incorporated intoa heterodimeric antibody of the invention may comprise a sequence ofcontiguous amino acids that differs from the sequence of a light chainin Table 7A or a heavy chain in Table 7B by 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15 or more amino acid residues, wherein each suchsequence difference is independently a deletion, insertion orsubstitution of one amino acid. In some embodiments, the anti-CGRPreceptor light chain incorporated into a heterodimeric antibodycomprises a sequence of amino acids that has at least 70%, at least 75%,at least 80%, at least 85%, at least 90%, at least 95%, at least 97% orat least 99% sequence identity to the amino acid sequences of SEQ IDNOs: 271-282 (i.e. the anti-CGRP receptor light chains in Table 7A). Incertain embodiments, the anti-CGRP receptor heavy chain incorporatedinto a heterodimeric antibody comprises a sequence of amino acids thathas at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95%, at least 97% or at least 99% sequence identity to theamino acid sequences of SEQ ID NOs: 295-316 (i.e. the anti-CGRP receptorheavy chains in Table 7B).

Any of the anti-PAC1 receptor light and heavy chains listed in Tables 6Aand 6B may be combined with any of the anti-CGRP receptor light andheavy chains listed in Table 7A and 7B to form a bispecific,heterodimeric antibody of the invention. The structural features (e.g.component anti-PAC1 receptor light and heavy chains and anti-CGRPreceptor light and heavy chains) of exemplary bispecific, heterodimericantibodies of the invention are set forth in Table 8 below. Theseantibodies contain one or more charge pair mutations as described hereinto promote correct pairing of heavy and light chains as well asheterodimerization between an anti-PAC1 receptor heavy chain and ananti-CGRP receptor heavy chain. Antibodies having an “A” designationcomprise the “v1” electrostatic steering strategy shown in FIG. 1,whereas antibodies having a “B” designation comprise the “v3”electrostatic steering strategy shown in FIG. 1. Antibodies having a “C”or “D” designation comprise the “v4” electrostatic steering strategyshown in FIG. 1, with “C” antibodies having an IgG1 constant domain and“D” antibodies having an IgG2 constant domain. The variable light andheavy chain designations (e.g. LV-01, LV-02, LV-101, LV-102, HV-01,HV-02, HV-101, HV-102, etc.) in Table 8 are defined by amino acidsequence in Tables 1A, 1B, 3A, and 3B and nucleotide sequence in Tables11 and 12. The light and heavy chain designations (e.g. LC-01, LC-02,LC-101, LC-102, HC-01, HC-02, HC-101, HC-102, etc.) in Table 8 aredefined by amino acid and nucleotide sequence in Tables 6A, 6B, 7A, and7B. Thus, the full sequence information for each of the four chains ofthe exemplary heterodimeric antibodies in Table 8 can be obtained bycross-reference to these tables. By way of illustration, heterodimericantibody iPS: 326417 comprises an anti-PAC1 receptor light chaincomprising the amino acid sequence of SEQ ID NO: 211 (LC-01), ananti-PAC1 receptor heavy chain comprising the amino acid sequence of SEQID NO: 233 (HC-01), an anti-CGRP receptor light chain comprising theamino acid sequence of SEQ ID NO: 281 (LC-111) and an anti-CGRP receptorheavy chain comprising the amino acid sequence of SEQ ID NO: 310(HC-116).

TABLE 8 Exemplary Anti-PAC1 Receptor/Anti-CGRP Receptor HeterodimericAntibodies Heterodimeric Anti-PAC1 Anti-PAC1 Anti-PAC1 Anti-PAC1Anti-PAC1 Anti-CGRP Anti- CGRP Anti- CGRP Anti- CGRP Anti- CGRP AntibodyReceptor Receptor Receptor Receptor Receptor Receptor Receptor ReceptorReceptor Receptor Designation Antibody ID. Full Light Chain VL FullHeavy Chain VH Antibody ID. Full Light Chain VL Full Heavy Chain VHiPS:326417 01A LC-01 LV-01 HC-01 HV-01 57A LC-111 LV-111 HC-116 HV-109iPS:326626 01D LC-01 LV-01 HC-04 HV-01 50D LC-101 LV-101 HC-104 HV-101iPS:326628 03D LC-04 LV-04 HC-08 HV-03 50D LC-101 LV-101 HC-104 HV-101iPS:326634 03D LC-04 LV-04 HC-08 HV-03 51D LC-103 LV-103 HC-108 HV-103iPS:327870 01D LC-01 LV-01 HC-04 HV-01 52D LC-105 LV-105 HC-112 HV-105iPS:327871 03D LC-04 LV-04 HC-08 HV-03 52D LC-105 LV-105 HC-112 HV-105iPS:326645 05D LC-08 LV-08 HC-16 HV-07 50D LC-101 LV-101 HC-104 HV-101iPS:326648 04D LC-06 LV-06 HC-12 HV-05 50D LC-101 LV-101 HC-104 HV-101iPS:326651 05D LC-08 LV-08 HC-16 HV-07 51D LC-103 LV-103 HC-108 HV-103iPS:326631 01D LC-01 LV-01 HC-04 HV-01 51D LC-103 LV-103 HC-108 HV-103iPS:326654 04D LC-06 LV-06 HC-12 HV-05 51D LC-103 LV-103 HC-108 HV-103iPS:328000 05D LC-08 LV-08 HC-16 HV-07 52D LC-105 LV-105 HC-112 HV-105iPS:328001 04D LC-06 LV-06 HC-12 HV-05 52D LC-105 LV-105 HC-112 HV-105iPS:326661 01D LC-01 LV-01 HC-04 HV-01 57D LC-111 LV-111 HC-119 HV-109iPS:326663 03D LC-04 LV-04 HC-08 HV-03 57D LC-111 LV-111 HC-119 HV-109iPS:326666 05D LC-08 LV-08 HC-16 HV-07 57D LC-111 LV-111 HC-119 HV-109iPS:326669 04D LC-06 LV-06 HC-12 HV-05 57D LC-111 LV-111 HC-119 HV-109iPS:327017 05A LC-08 LV-08 HC-13 HV-07 57A LC-111 LV-111 HC-116 HV-109iPS:327018 03A LC-04 LV-04 HC-05 HV-03 57A LC-111 LV-111 HC-116 HV-109iPS:327019 04A LC-06 LV-06 HC-09 HV-05 57A LC-111 LV-111 HC-116 HV-109iPS:327023 01B LC-02 LV-02 HC-02 HV-02 57B LC-112 LV-112 HC-117 HV-110iPS:327024 05B LC-09 LV-09 HC-14 HV-08 57B LC-112 LV-112 HC-117 HV-110iPS:327025 03B LC-05 LV-05 HC-06 HV-04 57B LC-112 LV-112 HC-117 HV-110iPS:327026 04B LC-07 LV-07 HC-10 HV-06 57B LC-112 LV-112 HC-117 HV-110iPS:327091 01C LC-01 LV-01 HC-03 HV-01 57C LC-111 LV-111 HC-118 HV-109iPS:327092 05C LC-08 LV-08 HC-15 HV-07 57C LC-111 LV-111 HC-118 HV-109iPS:327093 03C LC-04 LV-04 HC-07 HV-03 57C LC-111 LV-111 HC-118 HV-109iPS:327094 04C LC-06 LV-06 HC-11 HV-05 57C LC-111 LV-111 HC-118 HV-109iPS:326414 01A LC-01 LV-01 HC-01 HV-01 50A LC-101 LV-101 HC-101 HV-101iPS:327102 05A LC-08 LV-08 HC-13 HV-07 50A LC-101 LV-101 HC-101 HV-101iPS:327103 03A LC-04 LV-04 HC-05 HV-03 50A LC-101 LV-101 HC-101 HV-101iPS:327104 04A LC-06 LV-06 HC-09 HV-05 50A LC-101 LV-101 HC-101 HV-101iPS:327105 01B LC-02 LV-02 HC-02 HV-02 50B LC-102 LV-102 HC-102 HV-102iPS:327106 05B LC-09 LV-09 HC-14 HV-08 50B LC-102 LV-102 HC-102 HV-102iPS:327107 03B LC-05 LV-05 HC-06 HV-04 50B LC-102 LV-102 HC-102 HV-102iPS:327108 04B LC-07 LV-07 HC-10 HV-06 50B LC-102 LV-102 HC-102 HV-102iPS:327109 01C LC-01 LV-01 HC-03 HV-01 50C LC-101 LV-101 HC-103 HV-101iPS:327110 05C LC-08 LV-08 HC-15 HV-07 50C LC-101 LV-101 HC-103 HV-101iPS:327111 03C LC-04 LV-04 HC-07 HV-03 50C LC-101 LV-101 HC-103 HV-101iPS:327112 04C LC-06 LV-06 HC-11 HV-05 50C LC-101 LV-101 HC-103 HV-101iPS:327267 01A LC-01 LV-01 HC-01 HV-01 51A LC-103 LV-103 HC-105 HV-103iPS:327268 05A LC-08 LV-08 HC-13 HV-07 51A LC-103 LV-103 HC-105 HV-103iPS:327269 03A LC-04 LV-04 HC-05 HV-03 51A LC-103 LV-103 HC-105 HV-103iPS:327270 04A LC-06 LV-06 HC-09 HV-05 51A LC-103 LV-103 HC-105 HV-103iPS:327272 01B LC-02 LV-02 HC-02 HV-02 51B LC-104 LV-104 HC-106 HV-104iPS:327273 05B LC-09 LV-09 HC-14 HV-08 51B LC-104 LV-104 HC-106 HV-104iPS:327274 03B LC-05 LV-05 HC-06 HV-04 51B LC-104 LV-104 HC-106 HV-104iPS:327275 04B LC-07 LV-07 HC-10 HV-06 51B LC-104 LV-104 HC-106 HV-104iPS:327276 01C LC-01 LV-01 HC-03 HV-01 51C LC-103 LV-103 HC-107 HV-103iPS:327277 05C LC-08 LV-08 HC-15 HV-07 51C LC-103 LV-103 HC-107 HV-103iPS:327278 03C LC-04 LV-04 HC-07 HV-03 51C LC-103 LV-103 HC-107 HV-103iPS:327279 04C LC-06 LV-06 HC-11 HV-05 51C LC-103 LV-103 HC-107 HV-103iPS:327280 01A LC-01 LV-01 HC-01 HV-01 52A LC-105 LV-105 HC-109 HV-105iPS:327281 05A LC-08 LV-08 HC-13 HV-07 52A LC-105 LV-105 HC-109 HV-105iPS:327282 03A LC-04 LV-04 HC-05 HV-03 52A LC-105 LV-105 HC-109 HV-105iPS:327283 04A LC-06 LV-06 HC-09 HV-05 52A LC-105 LV-105 HC-109 HV-105iPS:327284 01B LC-02 LV-02 HC-02 HV-02 52B LC-106 LV-106 HC-110 HV-106iPS:327285 05B LC-09 LV-09 HC-14 HV-08 52B LC-106 LV-106 HC-110 HV-106iPS:327286 03B LC-05 LV-05 HC-06 HV-04 52B LC-106 LV-106 HC-110 HV-106iPS:327287 04B LC-07 LV-07 HC-10 HV-06 52B LC-106 LV-106 HC-110 HV-106iPS:327288 01C LC-01 LV-01 HC-03 HV-01 52C LC-105 LV-105 HC-111 HV-105iPS:327289 05C LC-08 LV-08 HC-15 HV-07 52C LC-105 LV-105 HC-111 HV-105iPS:327290 03C LC-04 LV-04 HC-07 HV-03 52C LC-105 LV-105 HC-111 HV-105iPS:327291 04C LC-06 LV-06 HC-11 HV-05 52C LC-105 LV-105 HC-111 HV-105iPS:327677 01A LC-01 LV-01 HC-01 HV-01 58A LC-111 LV-111 HC-120 HV-111iPS:327678 05A LC-08 LV-08 HC-13 HV-07 58A LC-111 LV-111 HC-120 HV-111iPS:327679 03A LC-04 LV-04 HC-05 HV-03 58A LC-111 LV-111 HC-120 HV-111iPS:327680 04A LC-06 LV-06 HC-09 HV-05 58A LC-111 LV-111 HC-120 HV-111iPS:327681 01B LC-02 LV-02 HC-02 HV-02 58B LC-112 LV-112 HC-121 HV-112iPS:327682 05B LC-09 LV-09 HC-14 HV-08 58B LC-112 LV-112 HC-121 HV-112iPS:327683 03B LC-05 LV-05 HC-06 HV-04 58B LC-112 LV-112 HC-121 HV-112iPS:327684 04B LC-07 LV-07 HC-10 HV-06 58B LC-112 LV-112 HC-121 HV-112iPS:327685 01C LC-01 LV-01 HC-03 HV-01 58C LC-111 LV-111 HC-122 HV-111iPS:327686 05C LC-08 LV-08 HC-15 HV-07 58C LC-111 LV-111 HC-122 HV-111iPS:327687 03C LC-04 LV-04 HC-07 HV-03 58C LC-111 LV-111 HC-122 HV-111iPS:327688 04C LC-06 LV-06 HC-11 HV-05 58C LC-111 LV-111 HC-122 HV-111iPS:327689 01A LC-01 LV-01 HC-01 HV-01 53A LC-105 LV-105 HC-113 HV-107iPS:327690 05A LC-08 LV-08 HC-13 HV-07 53A LC-105 LV-105 HC-113 HV-107iPS:327691 03A LC-04 LV-04 HC-05 HV-03 53A LC-105 LV-105 HC-113 HV-107iPS:327693 04A LC-06 LV-06 HC-09 HV-05 53A LC-105 LV-105 HC-113 HV-107iPS:327694 01B LC-02 LV-02 HC-02 HV-02 53B LC-106 LV-106 HC-114 HV-108iPS:327696 05B LC-09 LV-09 HC-14 HV-08 53B LC-106 LV-106 HC-114 HV-108iPS:327697 03B LC-05 LV-05 HC-06 HV-04 53B LC-106 LV-106 HC-114 HV-108iPS:327698 04B LC-07 LV-07 HC-10 HV-06 53B LC-106 LV-106 HC-114 HV-108iPS:327699 01C LC-01 LV-01 HC-03 HV-01 53C LC-105 LV-105 HC-115 HV-107iPS:327700 05C LC-08 LV-08 HC-15 HV-07 53C LC-105 LV-105 HC-115 HV-107iPS:327701 03C LC-04 LV-04 HC-07 HV-03 53C LC-105 LV-105 HC-115 HV-107iPS:327702 04C LC-06 LV-06 HC-11 HV-05 53C LC-105 LV-105 HC-115 HV-107iPS:327703 01A LC-01 LV-01 HC-01 HV-01 54A LC-107 LV-107 HC-109 HV-105iPS:327704 05A LC-08 LV-08 HC-13 HV-07 54A LC-107 LV-107 HC-109 HV-105iPS:327705 03A LC-04 LV-04 HC-05 HV-03 54A LC-107 LV-107 HC-109 HV-105iPS:327706 04A LC-06 LV-06 HC-09 HV-05 54A LC-107 LV-107 HC-109 HV-105iPS:327707 01B LC-02 LV-02 HC-02 HV-02 54B LC-108 LV-108 HC-110 HV-106iPS:327708 05B LC-09 LV-09 HC-14 HV-08 54B LC-108 LV-108 HC-110 HV-106iPS:327709 03B LC-05 LV-05 HC-06 HV-04 54B LC-108 LV-108 HC-110 HV-106iPS:327710 04B LC-07 LV-07 HC-10 HV-06 54B LC-108 LV-108 HC-110 HV-106iPS:327711 01C LC-01 LV-01 HC-03 HV-01 54C LC-107 LV-107 HC-111 HV-105iPS:327712 05C LC-08 LV-08 HC-15 HV-07 54C LC-107 LV-107 HC-111 HV-105iPS:327713 03C LC-04 LV-04 HC-07 HV-03 54C LC-107 LV-107 HC-111 HV-105iPS:327714 04C LC-06 LV-06 HC-11 HV-05 54C LC-107 LV-107 HC-111 HV-105iPS:327717 01A LC-01 LV-01 HC-01 HV-01 55A LC-109 LV-109 HC-109 HV-105iPS:327718 05A LC-08 LV-08 HC-13 HV-07 55A LC-109 LV-109 HC-109 HV-105iPS:327719 03A LC-04 LV-04 HC-05 HV-03 55A LC-109 LV-109 HC-109 HV-105iPS:327721 04A LC-06 LV-06 HC-09 HV-05 55A LC-109 LV-109 HC-109 HV-105iPS:327722 01B LC-02 LV-02 HC-02 HV-02 55B LC-110 LV-110 HC-110 HV-106iPS:327724 05B LC-09 LV-09 HC-14 HV-08 55B LC-110 LV-110 HC-110 HV-106iPS:327725 03B LC-05 LV-05 HC-06 HV-04 55B LC-110 LV-110 HC-110 HV-106iPS:327726 04B LC-07 LV-07 HC-10 HV-06 55B LC-110 LV-110 HC-110 HV-106iPS:327727 01C LC-01 LV-01 HC-03 HV-01 55C LC-109 LV-109 HC-111 HV-105iPS:327728 05C LC-08 LV-08 HC-15 HV-07 55C LC-109 LV-109 HC-111 HV-105iPS:327729 03C LC-04 LV-04 HC-07 HV-03 55C LC-109 LV-109 HC-111 HV-105iPS:327730 04C LC-06 LV-06 HC-11 HV-05 55C LC-109 LV-109 HC-111 HV-105iPS:327731 01A LC-01 LV-01 HC-01 HV-01 56A LC-107 LV-107 HC-113 LV-107iPS:327732 05A LC-08 LV-08 HC-13 HV-07 56A LC-107 LV-107 HC-113 LV-107iPS:327733 03A LC-04 LV-04 HC-05 HV-03 56A LC-107 LV-107 HC-113 LV-107iPS:327734 04A LC-06 LV-06 HC-09 HV-05 56A LC-107 LV-107 HC-113 LV-107iPS:327735 01B LC-02 LV-02 HC-02 HV-02 56B LC-108 LV-108 HC-114 LV-108iPS:327736 05B LC-09 LV-09 HC-14 HV-08 56B LC-108 LV-108 HC-114 LV-108iPS:327737 03B LC-05 LV-05 HC-06 HV-04 56B LC-108 LV-108 HC-114 LV-108iPS:327738 04B LC-07 LV-07 HC-10 HV-06 56B LC-108 LV-108 HC-114 LV-108iPS:327739 01C LC-01 LV-01 HC-03 HV-01 56C LC-107 LV-107 HC-115 LV-107iPS:327740 05C LC-08 LV-08 HC-15 HV-07 56C LC-107 LV-107 HC-115 LV-107iPS:327741 03C LC-04 LV-04 HC-07 HV-03 56C LC-107 LV-107 HC-115 LV-107iPS:327742 04C LC-06 LV-06 HC-11 HV-05 56C LC-107 LV-107 HC-115 LV-107iPS:327872 02A LC-03 LV-03 HC-01 HV-01 58A LC-111 LV-111 HC-120 HV-111iPS:327874 06A LC-10 LV-10 HC-17 HV-09 58A LC-111 LV-111 HC-120 HV-111iPS:327875 06B LC-11 LV-11 HC-18 HV-10 58B LC-112 LV-112 HC-121 HV-112iPS:327876 02C LC-03 LV-03 HC-03 HV-01 58C LC-111 LV-111 HC-122 HV-111iPS:327877 06C LC-10 LV-10 HC-19 HV-09 58C LC-111 LV-111 HC-122 HV-111iPS:327878 02A LC-03 LV-03 HC-01 HV-01 53A LC-105 LV-105 HC-113 HV-107iPS:327879 06A LC-10 LV-10 HC-17 HV-09 53A LC-105 LV-105 HC-113 HV-107iPS:327880 06B LC-11 LV-11 HC-18 HV-10 53B LC-106 LV-106 HC-114 HV-108iPS:327881 02C LC-03 LV-03 HC-03 HV-01 53C LC-105 LV-105 HC-115 HV-107iPS:327882 06C LC-10 LV-10 HC-19 HV-09 53C LC-105 LV-105 HC-115 HV-107iPS:327883 02A LC-03 LV-03 HC-01 HV-01 54A LC-107 LV-107 HC-109 HV-105iPS:327884 06A LC-10 LV-10 HC-17 HV-09 54A LC-107 LV-107 HC-109 HV-105iPS:327885 06B LC-11 LV-11 HC-18 HV-10 54B LC-108 LV-108 HC-110 HV-106iPS:327886 02C LC-03 LV-03 HC-03 HV-01 54C LC-107 LV-107 HC-111 HV-105iPS:327887 06C LC-10 LV-10 HC-19 HV-09 54C LC-107 LV-107 HC-111 HV-105iPS:327888 02A LC-03 LV-03 HC-01 HV-01 55A LC-109 LV-109 HC-109 HV-105iPS:327889 06A LC-10 LV-10 HC-17 HV-09 55A LC-109 LV-109 HC-109 HV-105iPS:327890 06B LC-11 LV-11 HC-18 HV-10 55B LC-110 LV-110 HC-110 HV-106iPS:327891 02C LC-03 LV-03 HC-03 HV-01 55C LC-109 LV-109 HC-111 HV-105iPS:327892 06C LC-10 LV-10 HC-19 HV-09 55C LC-109 LV-109 HC-111 HV-105iPS:327893 02A LC-03 LV-03 HC-01 HV-01 56A LC-107 LV-107 HC-113 LV-107iPS:327894 06A LC-10 LV-10 HC-17 HV-09 56A LC-107 LV-107 HC-113 LV-107iPS:327895 06B LC-11 LV-11 HC-18 HV-10 56B LC-108 LV-108 HC-114 LV-108iPS:327896 02C LC-03 LV-03 HC-03 HV-01 56C LC-107 LV-107 HC-115 LV-107iPS:327897 06C LC-10 LV-10 HC-19 HV-09 56C LC-107 LV-107 HC-115 LV-107iPS:328031 02A LC-03 LV-03 HC-01 HV-01 57A LC-111 LV-111 HC-116 HV-109iPS:328033 06A LC-10 LV-10 HC-17 HV-09 57A LC-111 LV-111 HC-116 HV-109iPS:328034 06B LC-11 LV-11 HC-18 HV-10 57B LC-112 LV-112 HC-117 HV-110iPS:328035 02C LC-03 LV-03 HC-03 HV-01 57C LC-111 LV-111 HC-118 HV-109iPS:328036 06C LC-10 LV-10 HC-19 HV-09 57C LC-111 LV-111 HC-118 HV-109iPS:328037 02A LC-03 LV-03 HC-01 HV-01 50A LC-101 LV-101 HC-101 HV-101iPS:328038 06A LC-10 LV-10 HC-17 HV-09 50A LC-101 LV-101 HC-101 HV-101iPS:328039 06B LC-11 LV-11 HC-18 HV-10 50B LC-102 LV-102 HC-102 HV-102iPS:328040 02C LC-03 LV-03 HC-03 HV-01 50C LC-101 LV-101 HC-103 HV-101iPS:328041 06C LC-10 LV-10 HC-19 HV-09 50C LC-101 LV-101 HC-103 HV-101iPS:328042 02A LC-03 LV-03 HC-01 HV-01 51A LC-103 LV-103 HC-105 HV-103iPS:328043 06A LC-10 LV-10 HC-17 HV-09 51A LC-103 LV-103 HC-105 HV-103iPS:328044 06B LC-11 LV-11 HC-18 HV-10 51B LC-104 LV-104 HC-106 HV-104iPS:328045 02C LC-03 LV-03 HC-03 HV-01 51C LC-103 LV-103 HC-107 HV-103iPS:328046 06C LC-10 LV-10 HC-19 HV-09 51C LC-103 LV-103 HC-107 HV-103iPS:328047 02A LC-03 LV-03 HC-01 HV-01 52A LC-105 LV-105 HC-109 HV-105iPS:328048 06A LC-10 LV-10 HC-17 HV-09 52A LC-105 LV-105 HC-109 HV-105iPS:328049 06B LC-11 LV-11 HC-18 HV-10 52B LC-106 LV-106 HC-110 HV-106iPS:328050 02C LC-03 LV-03 HC-03 HV-01 52C LC-105 LV-105 HC-111 HV-105iPS:328051 06C LC-10 LV-10 HC-19 HV-09 52C LC-105 LV-105 HC-111 HV-105

In certain embodiments, the bispecific antigen binding protein of theinvention is a heterodimeric antibody selected from the antibodiesdesignated as iPS:326417, iPS:326626, iPS:326628, iPS:326631,iPS:326634, iPS:327870, iPS:327871, iPS:326645, iPS:326648, iPS:326651,iPS:326654, iPS:328000, iPS:328001, iPS:326661, iPS:326663, iPS:326666,iPS:326669, iPS:327017, iPS:327018, iPS:327019, iPS:327023, iPS:327024,iPS:327025, iPS:327026, iPS:327091, iPS:327092, iPS:327093, iPS:327094,iPS:326414, iPS:327102, iPS:327103, iPS:327104, iPS:327105, iPS:327106,iPS:327107, iPS:327108, iPS:327109, iPS:327110, iPS:327111, iPS:327112,iPS:327267, iPS:327268, iPS:327269, iPS:327270, iPS:327272, iPS:327273,iPS:327274, iPS:327275, iPS:327276, iPS:327277, iPS:327278, iPS:327279,iPS:327280, iPS:327281, iPS:327282, iPS:327283, iPS:327284, iPS:327285,iPS:327286, iPS:327287, iPS:327288, iPS:327289, iPS:327290, iPS:327291,iPS:327677, iPS:327678, iPS:327679, iPS:327680, iPS:327681, iPS:327682,iPS:327683, iPS:327684, iPS:327685, iPS:327686, iPS:327687, iPS:327688,iPS:327689, iPS:327690, iPS:327691, iPS:327693, iPS:327694, iPS:327696,iPS:327697, iPS:327698, iPS:327699, iPS:327700, iPS:327701, iPS:327702,iPS:327703, iPS:327704, iPS:327705, iPS:327706, iPS:327707, iPS:327708,iPS:327709, iPS:327710, iPS:327711, iPS:327712, iPS:327713, iPS:327714,iPS:327717, iPS:327718, iPS:327719, iPS:327721, iPS:327722, iPS:327724,iPS:327725, iPS:327726, iPS:327727, iPS:327728, iPS:327729, iPS:327730,iPS:327731, iPS:327732, iPS:327733, iPS:327734, iPS:327735, iPS:327736,iPS:327737, iPS:327738, iPS:327739, iPS:327740, iPS:327741, iPS:327742,iPS:327872, iPS:327874, iPS:327875, iPS:327876, iPS:327877, iPS:327878,iPS:327879, iPS:327880, iPS:327881, iPS:327882, iPS:327883, iPS:327884,iPS:327885, iPS:327886, iPS:327887, iPS:327888, iPS:327889, iPS:327890,iPS:327891, iPS:327892, iPS:327893, iPS:327894, iPS:327895, iPS:327896,iPS:327897, iPS:328031, iPS:328033, iPS:328034, iPS:328035, iPS:328036,iPS:328037, iPS:328038, iPS:328039, iPS:328040, iPS:328041, iPS:328042,iPS:328043, iPS:328044, iPS:328045, iPS:328046, iPS:328047, iPS:328048,iPS:328049, iPS:328050, or iPS:328051 as set forth in Table 8. In someembodiments, the heterodimeric antibody is an antibody selected from theantibodies designated as iPS:327730, iPS:327680, iPS: 328001,iPS:327741, iPS:326648, iPS:327689, iPS:327111, iPS:327742, iPS:327698,iPS:327272, iPS:327717, iPS:327702, iPS:327270, iPS:327026, iPS:327112,iPS:327283, iPS:327688, or iPS:327714 as set forth in Table 8. In otherembodiments, the heterodimeric antibody is an antibody selected from theantibodies designated as iPS:327730, iPS:327680, iPS: 328001,iPS:327741, iPS:326648, iPS:327689, iPS:327111, iPS:327742, iPS:327698,iPS:327272, iPS:327717, iPS:327702, or iPS:327270 as set forth in Table8. In particular embodiments, the heterodimeric antibody is an antibodydesignated as iPS:327689 or iPS:327742 as set forth in Table 8.

The inventive heterodimeric antibodies also encompass antibodiescomprising the heavy chain(s) and/or light chain(s) described herein,where one, two, three, four or five amino acid residues are lacking fromthe N-terminus or C-terminus, or both, in relation to any one of theheavy and light chains set forth in Tables 6A, 6B, 7A, and 7B, e.g., dueto post-translational modifications resulting from the type of host cellin which the antibodies are expressed. For instance, Chinese HamsterOvary (CHO) cells frequently cleave off a C-terminal lysine fromantibody heavy chains.

In certain embodiments, the antigen binding proteins of the inventioncomprise (i) a first binding domain that specifically binds to humanCGRP receptor, (ii) a second binding domain that specifically binds tohuman PAC1 receptor, and (iii) a human immunoglobulin Fc region, whereinone of the binding domains is positioned at the amino terminus of the Fcregion and the other binding domain is positioned at the carboxylterminus of the Fc region. In some such embodiments, each of the firstand second binding domains comprises immunoglobulin variable regions.For instance, in certain embodiments, the first binding domain comprisesa first light chain variable region (VL1) and a first heavy chainvariable region (VH1) from an anti-CGRP receptor antibody and the secondbinding domain comprises a second light chain variable region (VL2) anda second heavy chain variable region (VH2) from an anti-PAC1 receptorantibody.

As used herein, the term “Fc region” refers to the C-terminal region ofan immunoglobulin heavy chain which may be generated by papain digestionof an intact antibody. The Fc region of an immunoglobulin generallycomprises two constant domains, a CH2 domain and a CH3 domain, andoptionally comprises a CH4 domain. In certain embodiments, the Fc regionis an Fc region from an IgG1, IgG2, IgG3, or IgG4 immunoglobulin. Insome embodiments, the Fc region comprises CH2 and CH3 domains from ahuman IgG1 or human IgG2 immunoglobulin. The Fc region may retaineffector function, such as C1q binding, complement dependentcytotoxicity (CDC), Fc receptor binding, antibody-dependentcell-mediated cytotoxicity (ADCC), and phagocytosis. In otherembodiments, the Fc region may be modified to reduce or eliminateeffector function as described in further detail herein.

In some embodiments of the antigen binding proteins of the invention,the binding domain positioned at the carboxyl terminus of the Fc region(i.e. the carboxyl-terminal binding domain) is a scFv. In certainembodiments, the scFv comprises a heavy chain variable region (VH) andlight chain variable region (VL) connected by a peptide linker. Thevariable regions may be oriented within the scFv in a VH-VL or VL-VHorientation. For instance, in one embodiment, the scFv comprises, fromN-terminus to C-terminus, a VH region, a peptide linker, and a VLregion. In another embodiment, the scFv comprises, from N-terminus toC-terminus, a VL region, a peptide linker, and a VH region. The VH andVL regions of the scFv may contain one or more cysteine substitutions topermit disulfide bond formation between the VH and VL regions. Suchcysteine clamps stabilize the two variable domains in theantigen-binding configuration. In one embodiment, position 44 (Kabatnumbering) in the VH region and position 100 (Kabat numbering) in the VLregion are each substituted with a cysteine residue.

In certain embodiments, the scFv is fused or otherwise connected at itsamino terminus to the carboxyl terminus of the Fc region (e.g. thecarboxyl terminus of the CH3 domain) through a peptide linker. Thus, inone embodiment, the scFv is fused to an Fc region such that theresulting fusion protein comprises, from N-terminus to C-terminus, a CH2domain, a CH3 domain, a first peptide linker, a VH region, a secondpeptide linker, and a VL region. In another embodiment, the scFv isfused to an Fc region such that the resulting fusion protein comprises,from N-terminus to C-terminus, a CH2 domain, a CH3 domain, a firstpeptide linker, a VL region, a second peptide linker, and a VH region. A“fusion protein” is a protein that includes polypeptide componentsderived from more than one parental protein or polypeptide. Typically, afusion protein is expressed from a fusion gene in which a nucleotidesequence encoding a polypeptide sequence from one protein is appended inframe with, and optionally separated by a linker from, a nucleotidesequence encoding a polypeptide sequence from a different protein. Thefusion gene can then be expressed by a recombinant host cell to producethe single fusion protein.

A “peptide linker” refers to an oligopeptide of about 2 to about 50amino acids that covalently joins one polypeptide to anotherpolypeptide. The peptide linkers can be used to connect the VH and VLdomains within the scFv. The peptide linkers can also be used to connecta scFv, Fab fragment, or other functional antibody fragment to the aminoterminus or carboxyl terminus of an Fc region to create bispecificantigen binding proteins as described herein. Preferably, the peptidelinkers are at least 5 amino acids in length. In certain embodiments,the peptide linkers are from about 5 amino acids in length to about 40amino acids in length. In other embodiments, the peptide linkers arefrom about 8 amino acids in length to about 30 amino acids in length. Instill other embodiments, the peptide linkers are from about 10 aminoacids in length to about 20 amino acids in length.

Preferably, but not necessarily, the peptide linker comprises aminoacids from among the twenty canonical amino acids, particularlycysteine, glycine, alanine, proline, asparagine, glutamine, and/orserine. In certain embodiments, the peptide linker is comprised of amajority of amino acids that are sterically unhindered, such as glycine,serine, and alanine. Thus, linkers that are preferred in someembodiments, include polyglycines, polyserines, and polyalanines, orcombinations of any of these. Some exemplary peptide linkers include,but are not limited to, poly(Gly)₂₋₈, particularly (Gly)₃, (Gly)₄ (SEQID NO: 362), (Gly)₅ (SEQ ID NO: 363) and (Gly)₇ (SEQ ID NO: 364), aswell as, poly(Gly)₄Ser (SEQ ID NO: 365), poly(Gly-Ala)₂₋₄ andpoly(Ala)₂₋₈. In certain embodiments, the peptide linker is(Gly_(x)Ser)_(n) where x=3 or 4 and n=2, 3, 4, 5 or 6. Such peptidelinkers include “L5” (GGGGS; or “G4S”; SEQ ID NO: 366), “L9” (GGGSGGGGS;or “G3SG4S”; SEQ ID NO: 367), “L10” (GGGGSGGGGS; or “(G4S)₂”; SEQ ID NO:368), “L15” (GGGGSGGGGSGGGGS; or “(G4S)₃”; SEQ ID NO: 369), and “L25”(GGGGSGGGGSGGGGSGGGGSGGGGS; or “(G4S)₅”; SEQ ID NO:370). In someembodiments, the peptide linker joining the VH and VL regions within thescFv is a L15 or (G4S)₃ linker (SEQ ID NO: 369). In these and otherembodiments, the peptide linker joining the carboxyl-terminal bindingdomain (e.g. scFv or Fab) to the C-terminus of the Fc region is a L9 orG3SG4S linker (SEQ ID NO: 367) or a L10 (G4S)₂ linker (SEQ ID NO: 368).

Other specific examples of peptide linkers that may be used in thebispecific antigen binding proteins of the invention include (Gly)₅Lys(SEQ ID NO: 371); (Gly)₅LysArg (SEQ ID NO: 372); (Gly)₃Lys(Gly)₄ (SEQ IDNO: 373); (Gly)₃AsnGlySer(Gly)₂ (SEQ ID NO: 374); (Gly)₃Cys(Gly)₄ (SEQID NO: 375); GlyProAsnGlyGly (SEQ ID NO: 376); GGEGGG (SEQ ID NO: 377);GGEEEGGG (SEQ ID NO: 378); GEEEG (SEQ ID NO: 379); GEEE (SEQ ID NO:380); GGDGGG (SEQ ID NO: 381); GGDDDGG (SEQ ID NO: 382); GDDDG (SEQ IDNO: 383); GDDD (SEQ ID NO: 384); GGGGSDDSDEGSDGEDGGGGS (SEQ ID NO: 385);WEWEW (SEQ ID NO: 386); FEFEF (SEQ ID NO: 387); EEEWWW (SEQ ID NO: 388);EEEFFF (SEQ ID NO: 389); WWEEEWW (SEQ ID NO: 390); and FFEEEFF (SEQ IDNO: 391).

In certain embodiments of the bispecific antigen binding proteins of theinvention, the binding domain positioned at the amino terminus of the Fcregion (i.e. the amino-terminal binding domain) is a Fab fragment fusedto the amino terminus of the Fc region through a peptide linkerdescribed herein or through an immunoglobulin hinge region. An“immunoglobulin hinge region” refers to the amino acid sequenceconnecting the CH1 domain and the CH2 domain of an immunoglobulin heavychain. The hinge region of human IgG1 is generally defined as the aminoacid sequence from about Glu216 or about Cys226, to about Pro230. Hingeregions of other IgG isotypes may be aligned with the IgG1 sequence byplacing the first and last cysteine residues forming inter-heavy chaindisulfide bonds in the same positions and are determinable to those ofskill in the art. In some embodiments, the amino-terminal binding domainis joined to the amino terminus of the Fc region through a human IgG1hinge region. In other embodiments, the amino-terminal binding domain isjoined to the amino terminus of the Fc region through a human IgG2 hingeregion. Preferably, the amino-terminal binding domain (e.g. Fabfragment) is fused to the Fc region through the carboxyl terminus of theCH1 region of the Fab.

In some embodiments, the bispecific antigen binding protein of theinvention comprises a first antibody that specifically binds to a firsttarget (e.g. human CGRP receptor or human PAC1 receptor) where a scFvcomprising variable domains from a second antibody that specificallybinds to a second target (e.g. human CGRP receptor or human PAC1receptor) is fused to the carboxyl terminus of the heavy chain of thefirst antibody. This format is referred to herein as the “IgG-scFv”format, and one embodiment of this type of molecule is shownschematically in FIG. 2. Thus, in certain embodiments, the presentinvention includes a bispecific, multivalent antigen binding proteincomprising: (i) a light chain and a heavy chain from a first antibody,and (ii) a scFv comprising VL and VH regions from a second antibody,wherein the scFv is fused at its amino terminus to the carboxyl terminusof the heavy chain through a peptide linker to form a modified heavychain, and wherein the first or second antibody specifically binds tohuman CGRP receptor and the other antibody specifically binds to humanPAC1 receptor. When dimerized, the bispecific antigen binding protein isa homotetramer comprising two light chains and two modified heavychains.

As used herein, the term “modified heavy chain” refers to a fusionprotein comprising an immunoglobulin heavy chain, particularly a humanIgG1 or human IgG2 heavy chain, and a functional antibody fragment (e.g.scFv, Fab) or portion thereof (e.g. immunoglobulin light chain or Fdfragment), wherein the fragment or portion thereof is fused at itsN-terminus, optionally through a peptide linker, to the C-terminus ofthe heavy chain.

In the IgG-scFv format of the bispecific antigen binding proteins of theinvention, an anti-PAC1 receptor antibody can be the first antibody(i.e. the “IgG”) or the second antibody (i.e. from which the scFv isderived). Similarly, an anti-CGRP receptor antibody can be the firstantibody (i.e. the “IgG”) or the second antibody (i.e. from which thescFv is derived). Any of the anti-PAC1 receptor antibody variableregions set forth in Tables 1A and 1B can be incorporated into eitherthe IgG component or the scFv component of the bispecific antigenbinding proteins of the invention. Any of the anti-CGRP receptorantibody variable regions set forth in Tables 3A and 3B can beincorporated into either the IgG component or the scFv component of thebispecific antigen binding proteins of the invention.

Amino acid sequences for light chains and modified heavy chains ofexemplary antigen binding proteins of the invention in the IgG-scFvformat are summarized in Table 9 below. The molecules listed in thefirst half of the table comprise an anti-PAC1 receptor IgG component andan anti-CGRP receptor scFv, whereas the molecules listed in the secondhalf of the table comprise an anti-CGRP receptor IgG component and ananti-PAC1 receptor scFv.

TABLE 9 Amino Acid Sequences of Exemplary Bispecific Antigen BindingProteins in the IgG-scFv Format IgG-scFv Light Chain Molecule Amino AcidModified Heavy Chain Amino Acid Designation Sequence SequenceAnti-PAC1 Receptor IgG x Anti-CGRP Receptor scFv iPS:386738DIQLTQSPSFLSASVGD QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPRVTITCRASQSIGRSLH GQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMEWYQQKPGKAPKLLIK LSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKYASQSLSGVPSRFSGS GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTGSGTEFTLTISSLQPED SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNFATYYCHQSSRLPFTF TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLGPGTKVDIKRTVAAPS MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCVFIFPPSDEQLKSGTAS EEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKVVCLLNNFYPREAKV TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIQWKVDNALQSGNSQE AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQSVTEQDSKDSTYSLSS GNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVETLTLSKADYEKHKVY SGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKCLEWACEVTHQGLSSPVTKS VAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDT FNRGECAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSG (SEQ ID NO: 392)GGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGCGTKLTVL (SEQ ID NO: 396) iPS:386764SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVLGGGGSGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSS (SEQ ID NO: 397) iPS:386762SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVLGGGGSGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSS (SEQ ID NO: 398) iPS:386760SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVLGGGGSGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSS (SEQ ID NO: 399) iPS:386758SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVLGGGGSGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSS (SEQ ID NO: 400) iPS:386756SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVLGGGGSGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSS (SEQ ID NO: 401) iPS:386754SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVL (SEQ ID NO: 402) iPS:386752SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVL (SEQ ID NO: 403) iPS:386750SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKCLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSRLSAVVFGCGTKLTVL (SEQ ID NO: 404) iPS:386748SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVL (SEQ ID NO: 405) iPS:386746SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVL (SEQ ID NO: 406) iPS:386744SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKCLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDSRLSAVVFGCGTKLTVL (SEQ ID NO: 407) iPS:386742SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKCLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSRLSAVVFGCGTKLTVL (SEQ ID NO: 408) iPS:386740SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKCLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGCGTKLTVL (SEQ ID NO: 409) iPS:386736SEQ ID NO: 392 QVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVL (SEQ ID NO: 410)Anti-CGRP Receptor IgG x Anti-PAC1 Receptor scFv iPS:386731QSVLTQPPSVSAAPGQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKVTISCSGSSSNIGNNY KGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSVSWYQQLPGTAPKLLI LRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTYDNNKRPSGIPDRFSG VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTSKSGTSTTLGITGLQTG VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYDEADYYCGTWDSRLS ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFAVVFGGGTKLTVLGQ LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEPKANPTVTLFPPSSEEL VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSQANKATLVCLISDFYP NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLGAVTVAWKADGSPVK VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTAGVETTKPSKQSNNK VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGYAASSYLSLTPEQWKS GGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGHRSYSCQVTHEGSTVE KAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATY KTVAPTECSYCHQSSRLPFTFGPGTKVDIKRGGGGSGGGGSGGGGSQVQLV (SEQ ID NO: 393)ESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSS (SEQ ID NO: 411) iPS:386725SEQ ID NO: 393 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRGGGGSGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSS (SEQ ID NO: 412) iPS:386717SEQ ID NO: 393 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKCPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGCGTKVDIKR (SEQ ID NO: 413) iPS:386715SEQ ID NO: 393 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKCPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGCGTKVDIKR (SEQ ID NO: 414) iPS:386707SEQ ID NO: 393 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKR (SEQ ID NO: 415) iPS:386705SEQ ID NO: 393 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKR (SEQ ID NO: 416) iPS:386723QSVLTQPPSVSAAPGQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKVTISCSGSSSNIGNNY KGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSVSWYQQLPGTAPKLLI LRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTYDNNKRPSGIPDRFSG VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTSKSGTSATLGITGLQT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYGDEADYYCGTWDSRL ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFSAVVFGGGTKLTVLG LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEQPKANPTVTLFPPSSEE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSLQANKATLVCLISDFY NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLPGAVTVAWKADGSPV VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTKAGVETTKPSKQSNN VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGKYAASSYLSLTPEQW GGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRKSHRSYSCQVTHEGST QAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTL VEKTVAPTECSYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSS (SEQ ID NO: 394)GGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKCPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGCGTKVDIKR (SEQ ID NO: 417) iPS:386719SEQ ID NO: 394 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKCPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGCGTKVDIKR (SEQ ID NO: 418) iPS:386713SEQ ID NO: 394 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKR (SEQ ID NO: 419) iPS:386709SEQ ID NO: 394 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKR (SEQ ID NO: 420) iPS:386727SEQ ID NO: 394 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRGGGGSGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSS (SEQ ID NO: 421) iPS:386721QSVLTQPPSVSAAPGQ QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKVTISCSGSSSNIGNNY KGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSVSWYQQLPGTAPKLLI LRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTYDNNKRPSGIPDRFSG VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTSKSGTSATLAITGLQT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYGDEADYYCGTWDSRL ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFSAVVFGGGTKLTVLG LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEQPKANPTVTLFPPSSEE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSLQANKATLVCLISDFY NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLPGAVTVAWKADGSPV VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTKAGVETTKPSKQSNN VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGKYAASSYLSLTPEQW GGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRKSHRSYSCQVTHEGST QAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTL VEKTVAPTECSYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSS (SEQ ID NO: 395)GGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKCPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGCGTKVDIKR (SEQ ID NO: 422) iPS:386711SEQ ID NO: 395 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKR (SEQ ID NO: 423) iPS:386733SEQ ID NO: 395 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRGGGGSGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSS (SEQ ID NO: 424) iPS:386729SEQ ID NO: 395 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRGGGGSGGGGSGGGGSQVQLVESGAEVVKPGASVKVSCKASGFTFSRFAMHWVRQAPGQGLEWMGVISYDGGNKYYAESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSS (SEQ ID NO: 425)

In certain embodiments, the first antibody (i.e. the IgG component) ofthe IgG-scFv bispecific antigen binding proteins is an anti-PAC1receptor antibody and the second antibody (i.e. from which the scFv isderived) is an anti-CGRP receptor antibody. In such embodiments, theanti-PAC1 receptor antibody comprises a VL region from any of thosedescribed in Table 1A and a VH region from any of those described inTable 1B. For instance, in one embodiment, the anti-PAC1 receptorantibody from which the IgG component is derived comprises a LV-04 (SEQID NO: 31) VL region and a HV-03 (SEQ ID NO: 85) VH region.

In embodiments in which the scFv component is derived from an anti-CGRPreceptor antibody, the anti-CGRP receptor antibody may comprise a VLregion from any of those described in Table 3A and a VH region from anyof those described in Table 3B. In one embodiment, the anti-CGRPreceptor scFv comprises a LV-105 (SEQ ID NO: 140) VL region and a HV-105(SEQ ID NO: 194) VH region. In another embodiment, the anti-CGRPreceptor scFv comprises a LV-105 (SEQ ID NO: 140) VL region and a HV-107(SEQ ID NO: 196) VH region. In another embodiment, the anti-CGRPreceptor scFv comprises a LV-107 (SEQ ID NO: 142) VL region and a HV-105(SEQ ID NO: 194) VH region. In yet another embodiment, the anti-CGRPreceptor scFv comprises a LV-109 (SEQ ID NO: 144) VL region and a HV-105(SEQ ID NO: 194) VH region. In still another embodiment, the anti-CGRPreceptor scFv comprises a LV-107 (SEQ ID NO: 142) VL region and a HV-107(SEQ ID NO: 196) VH region.

In embodiments in which the IgG component of the bispecific antigenbinding proteins is derived from an anti-PAC1 receptor antibody and thescFv component is derived from an anti-CGRP receptor antibody, themodified heavy chain of the bispecific antigen binding proteinscomprises a sequence selected from SEQ ID NOs: 396 to 410. In relatedembodiments, the light chain of the bispecific antigen binding proteinscomprises the sequence of SEQ ID NO: 392. In certain embodiments, thebispecific, multivalent antigen binding protein is an antigen bindingprotein designated as iPS:386738, iPS:386764, iPS:386762, iPS:386760,iPS:386758, iPS:386756, iPS:386754, iPS:386752, iPS:386750, iPS:386748,iPS:386746, iPS:386744, iPS:386742, iPS:386740, or iPS:386736 as setforth in Table 9. In other embodiments, the bispecific, multivalentantigen binding protein is an antigen binding protein designated asiPS:386738, iPS:386754, iPS:386750, iPS:386748, iPS:386746, iPS:386744,iPS:386740, or iPS:386736 as set forth in Table 9. In still otherembodiments, the bispecific, multivalent antigen binding protein is anantigen binding protein designated as iPS:386744, iPS:386746, oriPS:386748 as set forth in Table 9.

In other embodiments of the invention, the first antibody (i.e. the IgGcomponent) of the IgG-scFv bispecific antigen binding proteins is ananti-CGRP receptor antibody and the second antibody (i.e. from which thescFv is derived) is an anti-PAC1 receptor antibody. In such embodiments,the anti-CGRP receptor antibody comprises a VL region from any of thosedescribed in Table 3A and a VH region from any of those described inTable 3B. For example, in one embodiment, the anti-CGRP receptorantibody from which the IgG component is derived comprises a LV-105 (SEQID NO: 140) VL region and a HV-105 (SEQ ID NO: 194) VH region.

In another embodiment, the anti-CGRP receptor antibody from which theIgG component is derived comprises a LV-105 (SEQ ID NO: 140) VL regionand a HV-107 (SEQ ID NO: 196) VH region. In another embodiment, theanti-CGRP receptor antibody from which the IgG component is derivedcomprises a LV-107 (SEQ ID NO: 142) VL region and a HV-105 (SEQ ID NO:194) VH region. In yet another embodiment, the anti-CGRP receptorantibody from which the IgG component is derived comprises a LV-109 (SEQID NO: 144) VL region and a HV-105 (SEQ ID NO: 194) VH region. In stillanother embodiment, the anti-CGRP receptor antibody from which the IgGcomponent is derived comprises a LV-107 (SEQ ID NO: 142) VL region and aHV-107 (SEQ ID NO: 196) VH region.

In embodiments in which the scFv component is derived from an anti-PAC1receptor antibody, the anti-PAC1 receptor antibody may comprise a VLregion from any of those described in Table 1A and a VH region from anyof those described in Table 1B. In one embodiment, the anti-PAC1receptor scFv comprises a LV-04 (SEQ ID NO: 31) VL region and a HV-03(SEQ ID NO: 85) VH region.

In embodiments in which the IgG component of the bispecific antigenbinding proteins is derived from an anti-CGRP receptor antibody and thescFv component is derived from an anti-PAC1 receptor antibody, themodified heavy chain of the bispecific antigen binding proteinscomprises a sequence selected from SEQ ID NOs: 411 to 425. In relatedembodiments, the light chain of the bispecific antigen binding proteinscomprises a sequence selected from SEQ ID NOs: 393 to 395. In oneembodiment, the modified heavy chain comprises a sequence selected fromSEQ ID NOs: 411 to 416 and the light chain comprises the sequence of SEQID NO: 393.

In another embodiment, the modified heavy chain comprises a sequenceselected from SEQ ID NOs: 417 to 421 and the light chain comprises thesequence of SEQ ID NO: 394. In yet another embodiment, the modifiedheavy chain comprises a sequence selected from SEQ ID NOs: 422 to 425and the light chain comprises the sequence of SEQ ID NO: 395.

In certain embodiments, the bispecific, multivalent antigen bindingprotein is an antigen binding protein designated as iPS:386731,iPS:386725, iPS:386717, iPS:386715, iPS:386707, iPS:386705, iPS:386723,iPS:386719, iPS:386713, iPS:386709, iPS:386727, iPS:386721, iPS:386711,iPS:386733, or iPS:386729 as set forth in Table 9. In some embodiments,the bispecific, multivalent antigen binding protein is an antigenbinding protein designated as iPS:386721, iPS:386723, or iPS:386733 asset forth in Table 9.

In some embodiments of the antigen binding proteins of the invention,the binding domain positioned at the carboxyl terminus of the Fc region(i.e. the carboxyl-terminal binding domain) is a Fab fragment. In suchembodiments, the Fab is fused or otherwise connected to the carboxylterminus of the Fc region (e.g. the carboxyl terminus of the CH3 domain)through a peptide linker through the amino terminus of the VL region orVH region of the Fab fragment. Thus, in one embodiment, the Fab is fusedto an Fc region through the amino terminus of the VL region of the Fabsuch that the resulting fusion protein comprises, from N-terminus toC-terminus, a CH2 domain, a CH3 domain, a peptide linker, a VL region,and a CL region. In another embodiment, the Fab is fused to an Fc regionthrough the amino terminus of the VH region of the Fab such that theresulting fusion protein comprises, from N-terminus to C-terminus, a CH2domain, a CH3 domain, a peptide linker, a VH region, and a CH1 region.

The peptide linker joining the Fc region to the carboxyl-terminal Fabcan be any of the peptide linkers described herein. In particularembodiments, the peptide linker joining the Fc region to thecarboxyl-terminal Fab fragment is at least 5 amino acids in length. Inother embodiments, the peptide linker joining the Fc region to thecarboxyl-terminal Fab fragment is at least 8 amino acids in length.Particularly suitable peptide linkers for joining the Fc region to thecarboxyl-terminal Fab fragment are glycine-serine linkers, such as(Gly_(x)Ser)_(n) where x=3 or 4 and n=2, 3, 4, 5 or 6. In oneembodiment, the peptide linker connecting the Fc region to thecarboxyl-terminal Fab fragment is a L10 (G4S)₂ linker (SEQ ID NO: 368).In another embodiment, the peptide linker connecting the Fc region tothe carboxyl-terminal Fab fragment is a L9 or G3SG4S linker (SEQ ID NO:367).

In some embodiments of the bispecific antigen binding proteins of theinvention in which the carboxyl-terminal binding domain is a Fabfragment, the binding domain positioned at the amino terminus of the Fcregion (i.e. the amino-terminal binding domain) is also a Fab fragment.The amino-terminal Fab fragment can be fused to the amino terminus ofthe Fc region through a peptide linker or an immunoglobulin hinge regiondescribed herein. In some embodiments, the amino-terminal Fab fragmentis joined to the amino terminus of the Fc region through a human IgG1hinge region. In other embodiments, the amino-terminal Fab fragment isjoined to the amino terminus of the Fc region through a human IgG2 hingeregion. Preferably, the amino-terminal Fab fragment is fused to the Fcregion through the carboxyl terminus of the CH1 region of the Fab.

In some embodiments, the bispecific antigen binding protein of theinvention comprises a first antibody that specifically binds to a firsttarget (e.g. human CGRP receptor or human PAC1 receptor) where onepolypeptide chain (e.g. the light chain (VL-CL)) of a Fab fragment froma second antibody that specifically binds to a second target (e.g. humanCGRP receptor or human PAC1 receptor) is fused to the carboxyl terminusof the heavy chain of the first antibody. The bispecific antigen bindingprotein in such embodiments also comprises a polypeptide chaincontaining the other half of the Fab fragment from the second antibody(e.g. the Fd chain (VH-CH1)). This format is referred to herein as the“IgG-Fab” format, and one embodiment of this type of molecule is shownschematically in FIG. 3. Thus, in certain embodiments, the presentinvention includes a bispecific, multivalent antigen binding proteincomprising: (i) a light chain from a first antibody, (ii) a heavy chainfrom the first antibody, wherein the heavy chain is fused at itscarboxyl terminus through a peptide linker to a first polypeptidecomprising VL-CL domains or VH-CH1 domains of a second antibody to forma modified heavy chain, and (iii) a second polypeptide comprising VH-CH1domains or VL-CL domains of the second antibody, wherein the first orsecond antibody specifically binds to human CGRP receptor and the otherantibody specifically binds to human PAC1 receptor. When dimerized, thebispecific antigen binding protein is a homohexamer comprising twomodified heavy chains, two light chains from the first antibody, and twopolypeptide chains containing the other half of the Fab fragment fromthe second antibody (either the Fd fragment or light chain). In oneembodiment, the first polypeptide, which is fused to the carboxylterminus of the heavy chain, comprises VL and CL domains from the secondantibody, and the second polypeptide comprises VH and CH1 domains fromthe second antibody. In another embodiment, the first polypeptide, whichis fused to the carboxyl terminus of the heavy chain, comprises VH andCH1 domains from the second antibody, and the second polypeptidecomprises VL and CL domains from the second antibody.

Charge pair mutations or complimentary amino acid substitutions asdescribed herein can be introduced into the Fab regions of the firstantibody (Fab 1) or second antibody (Fab 2) to promote correct heavychain-light chain pairing. For instance, in some embodiments, the aminoacid at Kabat position 38 of the VL domain in Fab 1 is replaced with anegatively-charged amino acid (e.g. glutamic acid) and the amino acid atKabat position 39 of the VH domain in Fab 1 is replaced with apositively-charged amino acid (e.g. lysine). In other embodiments, theamino acid at Kabat position 38 of the VL domain in Fab 1 is replacedwith a positively-charged amino acid (e.g. lysine) and the amino acid atKabat position 39 of the VH domain in Fab 1 is replaced with anegatively-charged amino acid (e.g. glutamic acid). In certainembodiments, the amino acid at Kabat position 38 of the VL domain in Fab2 is replaced with a negatively-charged amino acid (e.g. glutamic acid)and the amino acid at Kabat position 39 of the VH domain in Fab 2 isreplaced with a positively-charged amino acid (e.g. lysine). In otherembodiments, the amino acid at Kabat position 38 of the VL domain in Fab2 is replaced with a positively-charged amino acid (e.g. lysine) and theamino acid at Kabat position 39 of the VH domain in Fab 2 is replacedwith a negatively-charged amino acid (e.g. glutamic acid).

In embodiments in which the VH-CH1 region (i.e. Fd fragment) from thesecond antibody is fused to the heavy chain of the first antibody, theheavy chain from the first antibody comprises a S183E mutation (EUnumbering), the light chain from the first antibody comprises a S176Kmutation (EU numbering), the light chain from the second antibodycomprises a S176E mutation (EU numbering), and the Fd region from thesecond antibody (which is fused to the C-terminus of the heavy chainfrom the first antibody) comprises a S183K mutation (EU numbering). Inother embodiments, the heavy chain from the first antibody comprises aG44E mutation (Kabat) and S183E mutation (EU numbering), the light chainfrom the first antibody comprises a G100K mutation (Kabat) and S176Kmutation (EU numbering), the light chain from the second antibodycomprises a G100E mutation (Kabat) and S176E mutation (EU numbering),and the Fd region from the second antibody (which is fused to theC-terminus of the heavy chain from the first antibody) comprises a G44Kmutation (Kabat) and S183K mutation (EU numbering). The charges in theforegoing examples may be reversed so long as the charge on thecorresponding light or heavy chain is also reversed so that the correctheavy/light chain pairs have opposite charges.

Additionally or alternatively, correct heavy-light chain pairing may befacilitated by swapping the CH1 and CL domains in the carboxyl-terminalFab binding domain. By way of example, the first polypeptide, which isfused to the carboxyl terminus of the heavy chain, may comprise a VLdomain and CH1 domain from the second antibody, and the secondpolypeptide may comprise a VH domain and CL domain from the secondantibody. In another embodiment, the first polypeptide, which is fusedto the carboxyl terminus of the heavy chain, may comprise a VH domainand a CL domain from the second antibody, and the second polypeptide maycomprise a VL domain and CH1 domain from the second antibody.

In the IgG-Fab format of the bispecific antigen binding proteins of theinvention, an anti-PAC1 receptor antibody can be the first antibody(i.e. the “IgG”) or the second antibody (i.e. from which the C-terminalFab is derived). Similarly, an anti-CGRP receptor antibody can be thefirst antibody (i.e. the “IgG”) or the second antibody (i.e. from whichthe C-terminal Fab is derived). Any of the anti-PAC1 receptor antibodyvariable regions set forth in Tables 1A and 1B can be incorporated intoeither the IgG component or the C-terminal Fab component of thebispecific antigen binding proteins of the invention. Any of theanti-CGRP receptor antibody variable regions set forth in Tables 3A and3B can be incorporated into either the IgG component or the C-terminalFab component of the bispecific antigen binding proteins of theinvention.

Amino acid sequences for light chains, modified heavy chains, and secondpolypeptides of exemplary antigen binding proteins of the invention inthe IgG-Fab format are summarized in Table 10 below. The moleculeslisted in the first half of the table comprise an anti-PAC1 receptor IgGcomponent and an anti-CGRP receptor C-terminal Fab fragment, whereas themolecules listed in the second half of the table comprise an anti-CGRPreceptor IgG component and an anti-PAC1 receptor C-terminal Fabfragment.

TABLE 10 Amino Acid Sequences of Exemplary Bispecific Antigen BindingProteins in the IgG-Fab Format Second IgG-Fab Light Chain PolypeptideMolecule Amino Acid Modified Heavy Chain Amino Acid Designation SequenceAmino Acid Sequence SequenceAnti-PAC1 Receptor IgG x Anti-CGRP Receptor Fab iPS:392513 DIQLTQSPSFLSAQVQLVESGAEVVKPGASVKVSCKASGFTFSRF QVQLVESGGGVVQP SVGDRVTITCRASAMHWVRQAPGQGLEWMGVISYDGGNKYYAE GRSLRLSCAASGFTF QSIGRSLHWYQQSVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY SSFGMHWVRQAPG KPGKAPKLLIKYYCARGYDVLTGYPDYWGQGTLVTVSSASTKG KGLEWVAVISFDGSI ASQSLSGVPSRFSPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT KYSVDSVKGRFTISR GSGSGTEFTLTISSVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT DNSKNTLFLQMNSL LQPEDFATYYCHVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS RAEDTAVYYCARDR QSSRLPFTFGPGTCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM LNYYDSSGYYHYKY KVDIKRTVAAPSISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV YGMAVWGQGTTVT VFIFPPSDEQLKSHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN VSSGQPKANPTVTLF GTASVVCLLNNFGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV PPSSEELQANKATLV YPREAKVQWKVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE CLISDFYPGAVTVA DNALQSGNSQESWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV WKADGSPVKAGVE VTEQDSKDSTYSDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL TTKPSKQSNNKYAA LESTLTLSKADYESPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS ESYLSLTPEQWKSH KHKVYACEVTHCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNN RSYSCQVTHEGSTV QGLSSPVTKSFNRKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD EKTVAPIECS GECYYCGTWDSRLSAVVFGGGTKLTVLASTKGPS (SEQ ID  (SEQ ID VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS NO: 452) NO: 214)WNSGALTSGVHTFPAVLQSSGLYSLKSVVTVP SSSLGTQTYICNVNHKPSNTKVDKKV(SEQ ID NO: 428) iPS:392514 SEQ ID  QVQLVESGAEVVKPGASVKVSCKASGFTFSRFQVQLVESGGGVVQP NO: 214 AMHWVRQAPGQGLEWMGVISYDGGNKYYAE GRSLRLSCAASGFTFSVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY SSFGMHWVREAPGKYCARGYDVLTGYPDYWGQGTLVTVSSASTKG GLEWVAVISFDGSIKPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT YSVDSVKGRFTISRDVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT NSKNTLFLQMNSLRVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS AEDTAVYYCARDRLCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM NYYDSSGYYHYKYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV YGMAVWGQGTTVTHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN VSSGQPKANPTVTLFGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV PPSSEELQANKATLVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE CLISDFYPGAVTVAWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV WKADGSPVKAGVEDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL TTKPSKQSNNKYAASPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS ESYLSLTPEQWKSHCSGSSSNIGNNYVSWYQKLPGTAPKLLIYDNN RSYSCQVTHEGSTVKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD EKTVAPTECSYYCGTWDSRLSAVVFGGGTKLTVLASTKGPS (SEQ ID VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS NO: 453)WNSGALTSGVHTFPAVLQSSGLYSLKSVVTVP SSSLGTQTYICNVNHKPSNTKVDKKV(SEQ ID NO: 429) iPS:392475 SEQ ID  QVQLVESGAEVVKPGASVKVSCKASGFTFSRFQVQLVESGGGVVQP NO: 214 AMHWVRQAPGQGLEWMGVISYDGGNKYYAE GRSLRLSCAASGFTFSVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY SSFGMHWVRQAPGYCARGYDVLTGYPDYWGQGTLVTVSSASTKG KGLEWVAVISFDGSIPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT KYSVDSVKGRFTISRVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT DNSKNTLFLQMNSLVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS RAEDTAVYYCARDRCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM LNYYESSGYYHYKYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV YGMAVWGQGTTVTHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN VSSGQPKANPTVTLFGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV PPSSEELQANKATLVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE CLISDFYPGAVTVAWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV WKADGSPVKAGVEDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL TTKPSKQSNNKYAASPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS ESYLSLTPEQWKSHCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNN RSYSCQVTHEGSTVKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD EKTVAPTECSYYCGTWDSRLSAVVFGGGTKLTVLASTKGPS (SEQ ID VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS NO: 454)WNSGALTSGVHTFPAVLQSSGLYSLKSVVTVP SSSLGTQTYICNVNHKPSNTKVDKKV(SEQ ID NO: 430) iPS:392519 SEQ ID  QVQLVESGAEVVKPGASVKVSCKASGFTFSRFQVQLVESGGGVVQP NO: 214 AMHWVRQAPGQGLEWMGVISYDGGNKYYAE GRSLRLSCAASGFTFSVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY SSFGMHWVREAPGKYCARGYDVLTGYPDYWGQGTLVTVSSASTKG GLEWVAVISFDGSIKPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT YSVDSVKGRFTISRDVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT NSKNTLFLQMNSLRVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS AEDTAVYYCARDRLCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM NYYESSGYYHYKYYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV GMAVWGQGTTVTVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN SSGQPKANPTVTLFPGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV PSSEELQANKATLVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE CLISDFYPGAVTVAWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV WKADGSPVKAGVEDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL TTKPSKQSNNKYAASPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS ESYLSLTPEQWKSHCSGSSSNIGNNYVSWYQKLPGTAPKLLIYDNN RSYSCQVTHEGSTVKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD EKTVAPTECSYYCGTWDSRLSAVVFGGGTKLTVLASTKGPS (SEQ ID VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS NO: 455)WNSGALTSGVHTFPAVLQSSGLYSLKSVVTVP SSSLGTQTYICNVNHKPSNTKVDKKV(SEQ ID NO: 431) iPS:392515 SEQ ID  QVQLVESGAEVVKPGASVKVSCKASGFTFSRFQVQLVESGGGVVQP NO: 214 AMHWVRQAPGQGLEWMGVISYDGGNKYYAE GRSLRLSCAASGFTFSVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY SSFGMHWVRQAPGYCARGYDVLTGYPDYWGQGTLVTVSSASTKG KGLEWVAVISFDGSIPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT KYSVDSVKGRFTISRVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT DNSKNTLFLQMNSLVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS RAEDTAVYYCARDRCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM LNYYDSSGYYHYKYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV YGMAVWGQGTTVTHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN VSSASTKGPSVFPLAGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV PSSKSTSGGTAALGCYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE LVKDYFPEPVTVSWWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV NSGALTSGVHTFPADKSRWQQGNVFSCSVMHEALHNHYTQKSLSL VLQSSGLYSLESVVTSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS VPSSSLGTQTYICNVCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNN NHKPSNTKVDKKVKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD (SEQ ID YYCGTWDSRLSAVVFGGGTKLTVLGQPKANP NO: 456)TVTLFPPSSEELQANKATLVCLISDFYPGAVTV AWKADGSPVKAGVETTKPSKQSNNKYAAKSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPT ECS (SEQ ID NO: 432) iPS:392516 SEQ ID QVQLVESGAEVVKPGASVKVSCKASGFTFSRF QVQLVESGGGVVQP NO: 214AMHWVRQAPGQGLEWMGVISYDGGNKYYAE GRSLRLSCAASGFTFSVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY SSFGMHWVREAPGKYCARGYDVLTGYPDYWGQGTLVTVSSASTKG GLEWVAVISFDGSIKPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT YSVDSVKGRFTISRDVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT NSKNTLFLQMNSLRVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS AEDTAVYYCARDRLCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM NYYDSSGYYHYKYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV YGMAVWGQGTTVTHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN VSSASTKGPSVFPLAGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV PSSKSTSGGTAALGCYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE LVKDYFPEPVTVSWWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV NSGALTSGVHTFPADKSRWQQGNVFSCSVMHEALHNHYTQKSLSL VLQSSGLYSLESVVTSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS VPSSSLGTQTYICNVCSGSSSNIGNNYVSWYQKLPGTAPKLLIYDNN NHKPSNTKVDKKVKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD (SEQ ID YYCGTWDSRLSAVVFGGGTKLTVLGQPKANP NO: 457)TVTLFPPSSEELQANKATLVCLISDFYPGAVTV AWKADGSPVKAGVETTKPSKQSNNKYAAKSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPT ECS (SEQ ID NO: 433) iPS:392521 SEQ ID QVQLVESGAEVVKPGASVKVSCKASGFTFSRF QVQLVESGGGVVQP NO: 214AMHWVRQAPGQGLEWMGVISYDGGNKYYAE GRSLRLSCAASGFTFSVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY SSFGMHWVREAPGKYCARGYDVLTGYPDYWGQGTLVTVSSASTKG GLEWVAVISFDGSIKPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT YSVDSVKGRFTISRDVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT NSKNTLFLQMNSLRVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS AEDTAVYYCARDRLCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM NYYESSGYYHYKYYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV GMAVWGQGTTVTVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN SSASTKGPSVFPLAPGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV SSKSTSGGTAALGCLYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE VKDYFPEPVTVSWNWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV SGALTSGVHTFPAVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL LQSSGLYSLESVVTVSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS PSSSLGTQTYICNVNCSGSSSNIGNNYVSWYQKLPGTAPKLLIYDNN HKPSNTKVDKKVKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD (SEQ ID YYCGTWDSRLSAVVFGGGTKLTVLGQPKANP NO: 458)TVTLFPPSSEELQANKATLVCLISDFYPGAVTV AWKADGSPVKAGVETTKPSKQSNNKYAAKSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPT ECS (SEQ ID NO: 434) iPS:392520 SEQ ID QVQLVESGAEVVKPGASVKVSCKASGFTFSRF QVQLVESGGGVVQP NO: 214AMHWVRQAPGQGLEWMGVISYDGGNKYYAE GRSLRLSCAASGFTFSVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY SSFGMHWVRQAPGYCARGYDVLTGYPDYWGQGTLVTVSSASTKG KGLEWVAVISFDGSIPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT KYSVDSVKGRFTISRVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT DNSKNTLFLQMNSLVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS RAEDTAVYYCARDRCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM LNYYESSGYYHYKYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV YGMAVWGQGTTVTHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN VSSASTKGPSVFPLAGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV PSSKSTSGGTAALGCYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE LVKDYFPEPVTVSWWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV NSGALTSGVHTFPADKSRWQQGNVFSCSVMHEALHNHYTQKSLSL VLQSSGLYSLESVVTSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS VPSSSLGTQTYICNVCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNN NHKPSNTKVDKKVKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD (SEQ ID YYCGTWDSRLSAVVFGGGTKLTVLGQPKANP NO: 459)TVTLFPPSSEELQANKATLVCLISDFYPGAVTV AWKADGSPVKAGVETTKPSKQSNNKYAAKSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPT ECS (SEQ ID NO: 435) iPS:392517DIQLTQSPSFLSA QVQLVESGAEVVKPGASVKVSCKASGFTFSRF SEQ ID  SVGDRVTITCRASAMHWVRKAPGQGLEWMGVISYDGGNKYYAE NO: 456 QSIGRSLHWYQESVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY KPGKAPKLLIKYYCARGYDVLTGYPDYWGQGTLVTVSSASTKG ASQSLSGVPSRFSPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT GSGSGTEFTLTISSVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT LQPEDFATYYCHVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS QSSRLPFTFGPGTCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM KVDIKRTVAAPSISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV VFIFPPSDEQLKSHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN GTASVVCLLNNFGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YPREAKVQWKVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE DNALQSGNSQESWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV VTEQDSKDSTYSDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL LESTLTLSKADYESPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS KHKVYACEVTHCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNN QGLSSPVTKSFNRKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD GEC YYCGTWDSRLSAVVFGGGTKLTVLGQPKANP(SEQ ID  TVTLFPPSSEELQANKATLVCLISDFYPGAVTV NO: 426)AWKADGSPVKAGVETTKPSKQSNNKYAAKSY LSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 436) iPS:392518 SEQ ID  QVQLVESGAEVVKPGASVKVSCKASGFTFSRFSEQ ID  NO: 426 AMHWVRKAPGQGLEWMGVISYDGGNKYYAE NO: 457SVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY YCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLKSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS CSGSSSNIGNNYVSWYQKLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD YYCGTWDSRLSAVVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTV AWKADGSPVKAGVETTKPSKQSNNKYAAKSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPT ECS (SEQ ID NO: 437) iPS:392522 SEQ ID QVQLVESGAEVVKPGASVKVSCKASGFTFSRF SEQ ID  NO: 426AMHWVRKAPGQGLEWMGVISYDGGNKYYAE NO: 459 SVKGRVTMTRDTSTSTLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNN KRPSGIPDRFSGSKSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVLGQPKANP TVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAKSY LSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 438) iPS:392523 SEQ ID  QVQLVESGAEVVKPGASVKVSCKASGFTFSRFSEQ ID  NO: 426 AMHWVRKAPGQGLEWMGVISYDGGNKYYAE NO: 458SVKGRVTMTRDTSTSTLYMELSSLRSEDTAVY YCARGYDVLTGYPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLKSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSQSVLTQPPSVSAAPGQKVTIS CSGSSSNIGNNYVSWYQKLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDEAD YYCGTWDSRLSAVVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTV AWKADGSPVKAGVETTKPSKQSNNKYAAKSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPT ECS (SEQ ID NO: 439)Anti-CGRP Receptor IgG x Anti-PAC1 Receptor Fab iPS:392524 QSVLTQPPSVSAAQVQLVESGGGVVQPGRSLRLSCAASGFTFSSF QVQLVESGAEVVKP PGQKVTISCSGSSGMHWVRQAPGKGLEWVAVISFDGSIKYSVDS GASVKVSCKASGFT SNIGNNYVSWYQVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYY FSRFAMHWVRQAP QLPGTAPKLLIYDCARDRLNYYDSSGYYHYKYYGMAVWGQGTT GQGLEWMGVISYD NNKRPSGIPDRFSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL GGNKYYAESVKGR GSKSGTSTTLGITVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS VTMTRDTSTSTLYM GLQTGDEADYYCGLYSLESVVTVPSSSLGTQTYICNVNHKPSNTK ELSSLRSEDTAVYYC GTWDSRLSAVVFVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF ARGYDVLTGYPDY GGGTKLTVLGQPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WGQGTLVTVSSTVA KANPTVTLFPPSSWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT APSVFIFPPSDEQLKS EELQANKATLVCVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA GTASVVCLLNNFYP LISDFYPGAVTVAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG REAKVQWKVDNAL WKADGSPVKAGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF QSGNSQESVTEQDS VETTKPSKQSNNFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH KDSTYSLKSTLTLSK KYAAKSYLSLTPYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSA ADYEKHKVYACEV EQWKSHRSYSCQSVGDRVTITCRASQSIGRSLHWYQQKPGKAPK THQGLSSPVTKSFNR VTHEGSTVEKTVLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQP GEC APTECSEDFATYYCHQSSRLPFTFGPGTKVDIKRASTKG (SEQ ID  (SEQ ID PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT NO: 460) NO: 275)VSWNSGALTSGVHTFPAVLQSSGLYSLESVVT VPSSSLGTQTYICNVNHKPSNTKVDKKV(SEQ ID NO: 440) iPS:392525 SEQ ID  QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFQVQLVESGAEVVKP NO: 275 GMHWVRQAPGKGLEWVAVISFDGSIKYSVDS GASVKVSCKASGFTVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYY FSRFAMHWVRKAPCARDRLNYYDSSGYYHYKYYGMAVWGQGTT GQGLEWMGVISYDVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL GGNKYYAESVKGRVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS VTMTRDTSTSTLYMGLYSLESVVTVPSSSLGTQTYICNVNHKPSNTK ELSSLRSEDTAVYYCVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF ARGYDVLTGYPDYPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WGQGTLVTVSSTVAWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT APSVFIFPPSDEQLKSVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA GTASVVCLLNNFYPKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG REAKVQWKVDNALFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF QSGNSQESVTEQDSFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH KDSTYSLKSTLTLSKYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSA ADYEKHKVYACEVSVGDRVTITCRASQSIGRSLHWYQEKPGKAPK THQGLSSPVTKSFNRLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQP GECEDFATYYCHQSSRLPFTFGPGTKVDIKRASTKG (SEQ ID PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT NO: 461)VSWNSGALTSGVHTFPAVLQSSGLYSLESVVT VPSSSLGTQTYICNVNHKPSNTKVDKKV(SEQ ID NO: 441) iPS:392526 SEQ ID  QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFSEQ ID  NO: 275 GMHWVRQAPGKGLEWVAVISFDGSIKYSVDS NO: 460VKGRFTISRDNSKNTLFLQMNSLRAEDTAVYY CARDRLNYYESSGYYHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLESVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSA SVGDRVTITCRASQSIGRSLHWYQQKPGKAPKLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQP EDFATYYCHQSSRLPFTFGPGTKVDIKRASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLESVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV (SEQ ID NO: 442) iPS:392527 SEQ ID QVQLVESGGGVVQPGRSLRLSCAASGFTFSSF SEQ ID  NO: 275GMHWVRQAPGKGLEWVAVISFDGSIKYSVDS NO: 461 VKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLESVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQEKPGKAPK LLIKYASQSLSGVPSRFSGSGSGYEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLESVVT VPSSSLGTQTYICNVNHKPSNTKVDKKV(SEQ ID NO: 443) iPS:392528 SEQ ID  QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFQVQLVESGAEVVKP NO: 275 GMHWVRQAPGKGLEWVAVISFDGSIKYSVDS GASVKVSCKASGFTVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYY FSRFAMHWVRQAPCARDRLNYYDSSGYYHYKYYGMAVWGQGTT GQGLEWMGVISYDVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL GGNKYYAESVKGRVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS VTMTRDTSTSTLYMGLYSLESVVTVPSSSLGTQTYICNVNHKPSNTK ELSSLRSEDTAVYYCVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF ARGYDVLTGYPDYPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WGQGTLVTVSSASTWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT KGPSVFPLAPSSKSTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA SGGTAALGCLVKDYKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FPEPVTVSWNSGALFYPSDAVEWESNGQPENNYKTTPPVLDSDGSF TSGVHTFPAVLQSSGFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH LYSLKSVVTVPSSSLYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSA GTQTYICNVNHKPSSVGDRVTITCRASQSIGRSLHWYQQKPGKAPK NTKVDKKVLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQP (SEQ ID EDFATYYCHQSSRLPFTFGPGTKVDIKRTVAAP NO: 462)SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLESTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC (SEQ ID NO: 444) iPS:392529SEQ ID  QVQLVESGGGVVQPGRSLRLSCAASGFTFSSF QVQLVESGAEVVKP NO: 275GMHWVRQAPGKGLEWVAVISFDGSIKYSVDS GASVKVSCKASGFTVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYY FSRFAMHWVRKAPCARDRLNYYDSSGYYHYKYYGMAVWGQGTT GQGLEWMGVISYDVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL GGNKYYAESVKGRVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS VTMTRDTSTSTLYMGLYSLESVVTVPSSSLGTQTYICNVNHKPSNTK ELSSLRSEDTAVYYCVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF ARGYDVLTGYPDYPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WGQGTLVTVSSASTWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT KGPSVFPLAPSSKSTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA SGGTAALGCLVKDYKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FPEPVTVSWNSGALFYPSDAVEWESNGQPENNYKTTPPVLDSDGSF TSGVHTFPAVLQSSGFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH LYSLKSVVTVPSSSLYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSA GTQTYICNVNHKPSSVGDRVTITCRASQSIGRSLHWYQEKPGKAPK NTKVDKKVLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQP (SEQ ID EDFATYYCHQSSRLPFTFGPGTKVDIKRTVAAP NO: 463)SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLESTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC (SEQ ID NO: 445) iPS:392532SEQ ID  QVQLVESGGGVVQPGRSLRLSCAASGFTFSSF SEQ ID  NO: 275GMHWVRQAPGKGLEWVAVISFDGSIKYSVDS NO: 462 VKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLESVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPK LLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLEST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 446) iPS:392533 SEQ ID QVQLVESGGGVVQPGRSLRLSCAASGFTFSSF SEQ ID  NO: 275GMHWVRQAPGKGLEWVAVISFDGSIKYSVDS NO: 463 VKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLESVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQEKPGKAPK LLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLEST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 447) iPS:392530 QSVLTQPPSVSAAQVQLVESGGGVVQPGRSLRLSCAASGFTFSSF SEQ ID  PGQKVTISCSGSSGMHWVREAPGKGLEWVAVISFDGSIKYSVDS NO: 462 SNIGNNYVSWYQVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYY KLPGTAPKLLIYDCARDRLNYYDSSGYYHYKYYGMAVWGQGTT NNKRPSGIPDRFSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL GSKSGTSTTLGITVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLQTGDEADYYCGLYSLESVVTVPSSSLGTQTYICNVNHKPSNTK GTWDSRLSAVVFVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF GGGTKLTVLGQPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN KANPTVTLFPPSSWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT EELQANKATLVCVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA LISDFYPGAVTVAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG WKADGSPVKAGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF VETTKPSKQSNNFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH KYAAKSYLSLTPYTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSA EQWKSHRSYSCQSVGDRVTITCRASQSIGRSLHWYQQKPGKAPK VTHEGSTVEKTVLLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQP APTECSEDFATYYCHQSSRLPFTFGPGTKVDIKRTVAAP (SEQ ID SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV NO: 427)QWKVDNALQSGNSQESVTEQDSKDSTYSLEST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 448) iPS:392531 SEQ ID QVQLVESGGGVVQPGRSLRLSCAASGFTFSSF SEQ ID  NO: 427GMHWVREAPGKGLEWVAVISFDGSIKYSVDS NO: 463 VKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLESVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQEKPGKAPK LLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLEST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 449) iPS:392534 SEQ ID QVQLVESGGGVVQPGRSLRLSCAASGFTFSSF SEQ ID  NO: 427GMHWVREAPGKGLEWVAVISFDGSIKYSVDS NO: 462 VKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLESVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQQKPGKAPK LLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLEST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 450) iPS:392535 SEQ ID QVQLVESGGGVVQPGRSLRLSCAASGFTFSSF SEQ ID  NO: 427GMHWVREAPGKGLEWVAVISFDGSIKYSVDS NO: 463 VKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYESSGYYHYKYYGMAVWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLESVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASQSIGRSLHWYQEKPGKAPK LLIKYASQSLSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCHQSSRLPFTFGPGTKVDIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLEST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 451)

In certain embodiments, the first antibody (i.e. the IgG component) ofthe IgG-Fab bispecific antigen binding proteins is an anti-PAC1 receptorantibody and the second antibody (i.e. from which the carboxyl-terminalFab is derived) is an anti-CGRP receptor antibody. In such embodiments,the anti-PAC1 receptor antibody comprises a VL region from any of thosedescribed in Table 1A and a VH region from any of those described inTable 1B. For instance, in one embodiment, the anti-PAC1 receptorantibody from which the IgG component is derived comprises a LV-04 (SEQID NO: 31) VL region and a HV-03 (SEQ ID NO: 85) VH region.

In embodiments in which the carboxyl-terminal Fab component is derivedfrom an anti-CGRP receptor antibody, the anti-CGRP receptor antibody maycomprise a VL region from any of those described in Table 3A and a VHregion from any of those described in Table 3B. In one embodiment, theanti-CGRP receptor Fab comprises a LV-105 (SEQ ID NO: 140) VL region anda HV-105 (SEQ ID NO: 194) VH region. In another embodiment, theanti-CGRP receptor Fab comprises a LV-105 (SEQ ID NO: 140) VL region anda HV-107 (SEQ ID NO: 196) VH region.

In embodiments in which the IgG component of the bispecific antigenbinding proteins is derived from an anti-PAC1 receptor antibody and thecarboxyl-terminal Fab component is derived from an anti-CGRP receptorantibody, the modified heavy chain of the bispecific antigen bindingproteins comprises a sequence selected from SEQ ID NOs: 428 to 439. Inrelated embodiments, the light chain of the bispecific antigen bindingproteins comprises the sequence of SEQ ID NO: 214 or SEQ ID NO: 426 andthe second polypeptide (which contains the other half of thecarboxyl-terminal Fab fragment) comprises a sequence selected from SEQID NOs: 452 to 459. In some embodiments, the bispecific, multivalentantigen binding protein comprises a light chain, a modified heavy chain,and a second polypeptide, wherein:

(a) the light chain comprises the sequence of SEQ ID NO: 214, themodified heavy chain comprises the sequence of SEQ ID NO: 428, and thesecond polypeptide comprises the sequence of SEQ ID NO: 452;

(b) the light chain comprises the sequence of SEQ ID NO: 214, themodified heavy chain comprises the sequence of SEQ ID NO: 429, and thesecond polypeptide comprises the sequence of SEQ ID NO: 453;

(c) the light chain comprises the sequence of SEQ ID NO: 214, themodified heavy chain comprises the sequence of SEQ ID NO: 430, and thesecond polypeptide comprises the sequence of SEQ ID NO: 454;

(d) the light chain comprises the sequence of SEQ ID NO: 214, themodified heavy chain comprises the sequence of SEQ ID NO: 431, and thesecond polypeptide comprises the sequence of SEQ ID NO: 455;

(e) the light chain comprises the sequence of SEQ ID NO: 214, themodified heavy chain comprises the sequence of SEQ ID NO: 432, and thesecond polypeptide comprises the sequence of SEQ ID NO: 456;

(f) the light chain comprises the sequence of SEQ ID NO: 214, themodified heavy chain comprises the sequence of SEQ ID NO: 433, and thesecond polypeptide comprises the sequence of SEQ ID NO: 457;

(g) the light chain comprises the sequence of SEQ ID NO: 214, themodified heavy chain comprises the sequence of SEQ ID NO: 434, and thesecond polypeptide comprises the sequence of SEQ ID NO: 458;

(h) the light chain comprises the sequence of SEQ ID NO: 214, themodified heavy chain comprises the sequence of SEQ ID NO: 435, and thesecond polypeptide comprises the sequence of SEQ ID NO: 459;

(i) the light chain comprises the sequence of SEQ ID NO: 426, themodified heavy chain comprises the sequence of SEQ ID NO: 436, and thesecond polypeptide comprises the sequence of SEQ ID NO: 456;

(j) the light chain comprises the sequence of SEQ ID NO: 426, themodified heavy chain comprises the sequence of SEQ ID NO: 437, and thesecond polypeptide comprises the sequence of SEQ ID NO: 457;

(k) the light chain comprises the sequence of SEQ ID NO: 426, themodified heavy chain comprises the sequence of SEQ ID NO: 438, and thesecond polypeptide comprises the sequence of SEQ ID NO: 459; or

(l) the light chain comprises the sequence of SEQ ID NO: 426, themodified heavy chain comprises the sequence of SEQ ID NO: 439, and thesecond polypeptide comprises the sequence of SEQ ID NO: 458. In certainembodiments, the bispecific, multivalent antigen binding protein is anantigen binding protein designated as iPS:392513, iPS:392514,iPS:392475, iPS:392519, iPS:392515, iPS:392516, iPS:392521, iPS:392520,iPS:392517, iPS:392518, iPS:392522, or iPS:392523 as set forth in Table10.

In other embodiments of the invention, the first antibody (i.e. the IgGcomponent) of the IgG-Fab bispecific antigen binding proteins is ananti-CGRP receptor antibody and the second antibody (i.e. from which thecarboxyl-terminal Fab is derived) is an anti-PAC1 receptor antibody. Insuch embodiments, the anti-CGRP receptor antibody comprises a VL regionfrom any of those described in Table 3A and a VH region from any ofthose described in Table 3B.

For example, in one embodiment, the anti-CGRP receptor antibody fromwhich the IgG component is derived comprises a LV-105 (SEQ ID NO: 140)VL region and a HV-105 (SEQ ID NO: 194) VH region. In anotherembodiment, the anti-CGRP receptor antibody from which the IgG componentis derived comprises a LV-105 (SEQ ID NO: 140) VL region and a HV-107(SEQ ID NO: 196) VH region. In embodiments in which thecarboxyl-terminal Fab component is derived from an anti-PAC1 receptorantibody, the anti-PAC1 receptor antibody may comprise a VL region fromany of those described in Table 1A and a VH region from any of thosedescribed in Table 1B. In one embodiment, the anti-PAC1 receptor Fabcomprises a LV-04 (SEQ ID NO: 31) VL region and a HV-03 (SEQ ID NO: 85)VH region.

In embodiments in which the IgG component of the bispecific antigenbinding proteins is derived from an anti-CGRP receptor antibody and thecarboxyl-terminal Fab component is derived from an anti-PAC1 receptorantibody, the modified heavy chain of the bispecific antigen bindingproteins comprises a sequence selected from SEQ ID NOs: 440 to 451. Inrelated embodiments, the light chain of the bispecific antigen bindingproteins comprises the sequence of SEQ ID NO: 275 or SEQ ID NO: 427 andthe second polypeptide (which contains the other half of thecarboxyl-terminal Fab fragment) comprises a sequence selected from SEQID NOs: 460 to 463. In some embodiments, the bispecific, multivalentantigen binding protein comprises a light chain, a modified heavy chain,and a second polypeptide, wherein:

(a) the light chain comprises the sequence of SEQ ID NO: 275, themodified heavy chain comprises the sequence of SEQ ID NO: 440, and thesecond polypeptide comprises the sequence of SEQ ID NO: 460;

(b) the light chain comprises the sequence of SEQ ID NO: 275, themodified heavy chain comprises the sequence of SEQ ID NO: 441, and thesecond polypeptide comprises the sequence of SEQ ID NO: 461;

(c) the light chain comprises the sequence of SEQ ID NO: 275, themodified heavy chain comprises the sequence of SEQ ID NO: 442, and thesecond polypeptide comprises the sequence of SEQ ID NO: 460;

(d) the light chain comprises the sequence of SEQ ID NO: 275, themodified heavy chain comprises the sequence of SEQ ID NO: 443, and thesecond polypeptide comprises the sequence of SEQ ID NO: 461;

(e) the light chain comprises the sequence of SEQ ID NO: 275, themodified heavy chain comprises the sequence of SEQ ID NO: 444, and thesecond polypeptide comprises the sequence of SEQ ID NO: 462;

(f) the light chain comprises the sequence of SEQ ID NO: 275, themodified heavy chain comprises the sequence of SEQ ID NO: 445, and thesecond polypeptide comprises the sequence of SEQ ID NO: 463;

(g) the light chain comprises the sequence of SEQ ID NO: 275, themodified heavy chain comprises the sequence of SEQ ID NO: 446, and thesecond polypeptide comprises the sequence of SEQ ID NO: 462;

(h) the light chain comprises the sequence of SEQ ID NO: 275, themodified heavy chain comprises the sequence of SEQ ID NO: 447, and thesecond polypeptide comprises the sequence of SEQ ID NO: 463;

(i) the light chain comprises the sequence of SEQ ID NO: 427, themodified heavy chain comprises the sequence of SEQ ID NO: 448, and thesecond polypeptide comprises the sequence of SEQ ID NO: 462;

(j) the light chain comprises the sequence of SEQ ID NO: 427, themodified heavy chain comprises the sequence of SEQ ID NO: 449, and thesecond polypeptide comprises the sequence of SEQ ID NO: 463;

(k) the light chain comprises the sequence of SEQ ID NO: 427, themodified heavy chain comprises the sequence of SEQ ID NO: 450, and thesecond polypeptide comprises the sequence of SEQ ID NO: 462; or

(l) the light chain comprises the sequence of SEQ ID NO: 427, themodified heavy chain comprises the sequence of SEQ ID NO: 451, and thesecond polypeptide comprises the sequence of SEQ ID NO: 463. In certainembodiments, the bispecific, multivalent antigen binding protein is anantigen binding protein designated as iPS:392524, iPS:392525,iPS:392526, iPS:392527, iPS:392528, iPS:392529, iPS:392532, iPS:392533,iPS:392530, iPS:392531, iPS:392534, or iPS:392535 as set forth in Table10. In other embodiments, the bispecific, multivalent antigen bindingprotein is an antigen binding protein designated as iPS:392524,iPS:392525, iPS:392526, iPS:392527, iPS:392532, iPS:392533, iPS:392534,or iPS:392535 as set forth in Table 10.

The heavy chain constant regions or the Fc regions of the bispecificantigen binding proteins described herein may comprise one or more aminoacid substitutions that affect the glycosylation and/or effectorfunction of the antigen binding protein. One of the functions of the Fcregion of an immunoglobulin is to communicate to the immune system whenthe immunoglobulin binds its target. This is commonly referred to as“effector function.” Communication leads to antibody-dependent cellularcytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP),and/or complement dependent cytotoxicity (CDC). ADCC and ADCP aremediated through the binding of the Fc region to Fc receptors on thesurface of cells of the immune system. CDC is mediated through thebinding of the Fc with proteins of the complement system, e.g., C1q. Insome embodiments, the bispecific antigen binding proteins of theinvention comprise one or more amino acid substitutions in the constantregion to enhance effector function, including ADCC activity, CDCactivity, ADCP activity, and/or the clearance or half-life of theantigen binding protein. Exemplary amino acid substitutions (EUnumbering) that can enhance effector function include, but are notlimited to, E233L, L234I, L234Y, L235S, G236A, S239D, F243L, F243V,P247I, D280H, K290S, K290E, K290N, K290Y, R292P, E294L, Y296W, S298A,S298D, S298V, S298G, S298T, T299A, Y300L, V305I, Q311M, K326A, K326E,K326W, A330S, A330L, A330M, A330F, I332E, D333A, E333S, E333A, K334A,K334V, A339D, A339Q, P396L, or combinations of any of the foregoing.

In other embodiments, the bispecific antigen binding proteins of theinvention comprise one or more amino acid substitutions in the constantregion to reduce effector function. Exemplary amino acid substitutions(EU numbering) that can reduce effector function include, but are notlimited to, C220S, C226S, C229S, E233P, L234A, L234V, V234A, L234F,L235A, L235E, G237A, P238S, S267E, H268Q, N297A, N297G, V309L, E318A,L328F, A330S, A331 S, P331S or combinations of any of the foregoing.

Glycosylation can contribute to the effector function of antibodies,particularly IgG1 antibodies. Thus, in some embodiments, the bispecificantigen binding proteins of the invention may comprise one or more aminoacid substitutions that affect the level or type of glycosylation of thebinding proteins. Glycosylation of polypeptides is typically eitherN-linked or O-linked. N-linked refers to the attachment of thecarbohydrate moiety to the side chain of an asparagine residue. Thetri-peptide sequences asparagine-X-serine and asparagine-X-threonine,where X is any amino acid except proline, are the recognition sequencesfor enzymatic attachment of the carbohydrate moiety to the asparagineside chain. Thus, the presence of either of these tri-peptide sequencesin a polypeptide creates a potential glycosylation site. O-linkedglycosylation refers to the attachment of one of the sugarsN-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid,most commonly serine or threonine, although 5-hydroxyproline or5-hydroxylysine may also be used.

In certain embodiments, glycosylation of the bispecific antigen bindingproteins described herein is increased by adding one or moreglycosylation sites, e.g., to the Fc region of the binding protein.Addition of glycosylation sites to the antigen binding protein can beconveniently accomplished by altering the amino acid sequence such thatit contains one or more of the above-described tri-peptide sequences(for N-linked glycosylation sites). The alteration may also be made bythe addition of, or substitution by, one or more serine or threonineresidues to the starting sequence (for O-linked glycosylation sites).For ease, the antigen binding protein amino acid sequence may be alteredthrough changes at the DNA level, particularly by mutating the DNAencoding the target polypeptide at preselected bases such that codonsare generated that will translate into the desired amino acids.

The invention also encompasses production of bispecific antigen bindingprotein molecules with altered carbohydrate structure resulting inaltered effector activity, including antigen binding proteins withabsent or reduced fucosylation that exhibit improved ADCC activity.Various methods are known in the art to reduce or eliminatefucosylation. For example, ADCC effector activity is mediated by bindingof the antibody molecule to the FcγRIII receptor, which has been shownto be dependent on the carbohydrate structure of the N-linkedglycosylation at the N297 residue of the CH2 domain. Non-fucosylatedantibodies bind this receptor with increased affinity and triggerFcγRIII-mediated effector functions more efficiently than native,fucosylated antibodies. For example, recombinant production ofnon-fucosylated antibody in CHO cells in which the alpha-1,6-fucosyltransferase enzyme has been knocked out results in antibody with100-fold increased ADCC activity (see Yamane-Ohnuki et al., BiotechnolBioeng. 87(5):614-22, 2004). Similar effects can be accomplished throughdecreasing the activity of alpha-1,6-fucosyl transferase enzyme or otherenzymes in the fucosylation pathway, e.g., through siRNA or antisenseRNA treatment, engineering cell lines to knockout the enzyme(s), orculturing with selective glycosylation inhibitors (see Rothman et al.,Mol Immunol. 26(12): 1113-23, 1989). Some host cell strains, e.g. Lec13or rat hybridoma YB2/0 cell line naturally produce antibodies with lowerfucosylation levels (see Shields et al., J Biol Chem. 277(30):26733-40,2002 and Shinkawa et al., J Biol Chem. 278(5):3466-73, 2003). Anincrease in the level of bisected carbohydrate, e.g. throughrecombinantly producing antibody in cells that overexpress GnTIIIenzyme, has also been determined to increase ADCC activity (see Umana etal., Nat Biotechnol. 17(2): 176-80, 1999).

In other embodiments, glycosylation of the bispecific antigen bindingproteins described herein is decreased or eliminated by removing one ormore glycosylation sites, e.g., from the Fc region of the bindingprotein. Amino acid substitutions that eliminate or alter N-linkedglycosylation sites can reduce or eliminate N-linked glycosylation ofthe antigen binding protein.

In certain embodiments, the bispecific antigen binding proteinsdescribed herein comprise a mutation at position N297 (EU numbering),such as N297Q, N297A, or N297G. In one particular embodiment, thebispecific antigen binding proteins of the invention comprise a Fcregion from a human IgG1 antibody with a N297G mutation. To improve thestability of molecules comprising a N297 mutation, the Fc region of themolecules may be further engineered. For instance, in some embodiments,one or more amino acids in the Fc region are substituted with cysteineto promote disulfide bond formation in the dimeric state. Residuescorresponding to V259, A287, R292, V302, L306, V323, or I332 (EUnumbering) of an IgG1 Fc region may thus be substituted with cysteine.Preferably, specific pairs of residues are substituted with cysteinesuch that they preferentially form a disulfide bond with each other,thus limiting or preventing disulfide bond scrambling. Preferred pairsinclude, but are not limited to, A287C and L306C, V259C and L306C, R292Cand V302C, and V323C and I332C. In particular embodiments, thebispecific antigen binding proteins described herein comprise a Fcregion from a human IgG1 antibody with mutations at R292C and V302C. Insuch embodiments, the Fc region may also comprise a N297G mutation.

Modifications of the bispecific antigen binding proteins of theinvention to increase serum half-life also may desirable, for example,by incorporation of or addition of a salvage receptor binding epitope(e.g., by mutation of the appropriate region or by incorporating theepitope into a peptide tag that is then fused to the antigen bindingprotein at either end or in the middle, e.g., by DNA or peptidesynthesis; see, e.g., WO96/32478) or adding molecules such as PEG orother water soluble polymers, including polysaccharide polymers. Thesalvage receptor binding epitope preferably constitutes a region whereinany one or more amino acid residues from one or two loops of a Fc regionare transferred to an analogous position in the antigen binding protein.Even more preferably, three or more residues from one or two loops ofthe Fc region are transferred. Still more preferred, the epitope istaken from the CH2 domain of the Fc region (e.g., an IgG Fc region) andtransferred to the CH1, CH3, or VH region, or more than one such region,of the antigen binding protein. Alternatively, the epitope is taken fromthe CH2 domain of the Fc region and transferred to the CL region or VLregion, or both, of the antigen binding protein. See Internationalapplications WO 97/34631 and WO 96/32478 for a description of Fcvariants and their interaction with the salvage receptor.

The present invention includes one or more isolated nucleic acidsencoding the bispecific antigen binding proteins and components thereofdescribed herein. Nucleic acid molecules of the invention include DNAand RNA in both single-stranded and double-stranded form, as well as thecorresponding complementary sequences. DNA includes, for example, cDNA,genomic DNA, chemically synthesized DNA, DNA amplified by PCR, andcombinations thereof. The nucleic acid molecules of the inventioninclude full-length genes or cDNA molecules as well as a combination offragments thereof. The nucleic acids of the invention are preferentiallyderived from human sources, but the invention includes those derivedfrom non-human species, as well.

Relevant amino acid sequences from an immunoglobulin or region thereof(e.g. variable region, Fc region, etc.) or polypeptide of interest maybe determined by direct protein sequencing, and suitable encodingnucleotide sequences can be designed according to a universal codontable. Alternatively, genomic or cDNA encoding monoclonal antibodiesfrom which the binding domains of the bispecific antigen bindingproteins of the invention may be derived can be isolated and sequencedfrom cells producing such antibodies using conventional procedures(e.g., by using oligonucleotide probes that are capable of bindingspecifically to genes encoding the heavy and light chains of themonoclonal antibodies).

An “isolated nucleic acid,” which is used interchangeably herein with“isolated polynucleotide,” is a nucleic acid that has been separatedfrom adjacent genetic sequences present in the genome of the organismfrom which the nucleic acid was isolated, in the case of nucleic acidsisolated from naturally-occurring sources. In the case of nucleic acidssynthesized enzymatically from a template or chemically, such as PCRproducts, cDNA molecules, or oligonucleotides for example, it isunderstood that the nucleic acids resulting from such processes areisolated nucleic acids. An isolated nucleic acid molecule refers to anucleic acid molecule in the form of a separate fragment or as acomponent of a larger nucleic acid construct.

In one preferred embodiment, the nucleic acids are substantially freefrom contaminating endogenous material. The nucleic acid molecule haspreferably been derived from DNA or RNA isolated at least once insubstantially pure form and in a quantity or concentration enablingidentification, manipulation, and recovery of its component nucleotidesequences by standard biochemical methods (such as those outlined inSambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., ColdSpring Harbor Laboratory, Cold Spring Harbor, N.Y. (1989)). Suchsequences are preferably provided and/or constructed in the form of anopen reading frame uninterrupted by internal non-translated sequences,or introns, that are typically present in eukaryotic genes. Sequences ofnon-translated DNA can be present 5′ or 3′ from an open reading frame,where the same do not interfere with manipulation or expression of thecoding region. Unless specified otherwise, the left-hand end of anysingle-stranded polynucleotide sequence discussed herein is the 5′ end;the left-hand direction of double-stranded polynucleotide sequences isreferred to as the 5′ direction. The direction of 5′ to 3′ production ofnascent RNA transcripts is referred to as the transcription direction;sequence regions on the DNA strand having the same sequence as the RNAtranscript that are 5′ to the 5′ end of the RNA transcript are referredto as “upstream sequences;” sequence regions on the DNA strand havingthe same sequence as the RNA transcript that are 3′ to the 3′ end of theRNA transcript are referred to as “downstream sequences.”

The present invention also includes nucleic acids that hybridize undermoderately stringent conditions, and more preferably highly stringentconditions, to nucleic acids encoding polypeptides as described herein.The basic parameters affecting the choice of hybridization conditionsand guidance for devising suitable conditions are set forth by Sambrook,Fritsch, and Maniatis (1989, Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters9 and 11; and Current Protocols in Molecular Biology, 1995, Ausubel etal., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4), and canbe readily determined by those having ordinary skill in the art basedon, for example, the length and/or base composition of the DNA. One wayof achieving moderately stringent conditions involves the use of aprewashing solution containing 5×SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0),hybridization buffer of about 50% formamide, 6×SSC, and a hybridizationtemperature of about 55° C. (or other similar hybridization solutions,such as one containing about 50% formamide, with a hybridizationtemperature of about 42° C.), and washing conditions of about 60° C., in0.5×SSC, 0.1% SDS. Generally, highly stringent conditions are defined ashybridization conditions as above, but with washing at approximately 68°C., 0.2×SSC, 0.1% SDS. SSPE (1×SSPE is 0.15M NaCl, 10 mM NaH₂PO₄, and1.25 mM EDTA, pH 7.4) can be substituted for SSC (1×SSC is 0.15M NaCland 15 mM sodium citrate) in the hybridization and wash buffers; washesare performed for 15 minutes after hybridization is complete. It shouldbe understood that the wash temperature and wash salt concentration canbe adjusted as necessary to achieve a desired degree of stringency byapplying the basic principles that govern hybridization reactions andduplex stability, as known to those skilled in the art and describedfurther below (see, e.g., Sambrook et al., 1989). When hybridizing anucleic acid to a target nucleic acid of unknown sequence, the hybridlength is assumed to be that of the hybridizing nucleic acid. Whennucleic acids of known sequence are hybridized, the hybrid length can bedetermined by aligning the sequences of the nucleic acids andidentifying the region or regions of optimal sequence complementarity.The hybridization temperature for hybrids anticipated to be less than 50base pairs in length should be 5 to 10° C. less than the meltingtemperature (Tm) of the hybrid, where Tm is determined according to thefollowing equations. For hybrids less than 18 base pairs in length, Tm(° C.)=2(# of A+T bases)+4(# of G+C bases). For hybrids above 18 basepairs in length, Tm (° C.)=81.5+16.6(log 10 [Na+])+0.41(% G+C)−(600/N),where N is the number of bases in the hybrid, and [Na+] is theconcentration of sodium ions in the hybridization buffer ([Na+] for1×SSC=0.165M). Preferably, each such hybridizing nucleic acid has alength that is at least 15 nucleotides (or more preferably at least 18nucleotides, or at least 20 nucleotides, or at least 25 nucleotides, orat least 30 nucleotides, or at least 40 nucleotides, or most preferablyat least 50 nucleotides), or at least 25% (more preferably at least 50%,or at least 60%, or at least 70%, and most preferably at least 80%) ofthe length of the nucleic acid of the present invention to which ithybridizes, and has at least 60% sequence identity (more preferably atleast 70%, at least 75%, at least 80%, at least 81%, at least 82%, atleast 83%, at least 84%, at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, or at least 99%, and most preferably at least 99.5%) with thenucleic acid of the present invention to which it hybridizes, wheresequence identity is determined by comparing the sequences of thehybridizing nucleic acids when aligned so as to maximize overlap andidentity while minimizing sequence gaps as described in more detailabove.

Variants of the antigen binding proteins described herein can beprepared by site-specific mutagenesis of nucleotides in the DNA encodingthe polypeptide, using cassette or PCR mutagenesis or other techniqueswell known in the art, to produce DNA encoding the variant, andthereafter expressing the recombinant DNA in cell culture as outlinedherein. However, antigen binding proteins comprising variant CDRs havingup to about 100-150 residues may be prepared by in vitro synthesis usingestablished techniques. The variants typically exhibit the samequalitative biological activity as the naturally occurring analogue,e.g., binding to antigen. Such variants include, for example, deletionsand/or insertions and/or substitutions of residues within the amino acidsequences of the antigen binding proteins. Any combination of deletion,insertion, and substitution is made to arrive at the final construct,provided that the final construct possesses the desired characteristics.The amino acid changes also may alter post-translational processes ofthe antigen binding protein, such as changing the number or position ofglycosylation sites. In certain embodiments, antigen binding proteinvariants are prepared with the intent to modify those amino acidresidues which are directly involved in epitope binding. In otherembodiments, modification of residues which are not directly involved inepitope binding or residues not involved in epitope binding in any way,is desirable, for purposes discussed herein. Mutagenesis within any ofthe CDR regions and/or framework regions is contemplated.

Covariance analysis techniques can be employed by the skilled artisan todesign useful modifications in the amino acid sequence of the antigenbinding protein. See, e.g., Choulier, et al., Proteins 41:475-484, 2000;Demarest et al., J. Mol. Biol. 335:41-48, 2004; Hugo et al., ProteinEngineering 16(5):381-86, 2003; Aurora et al., US Patent Publication No.2008/0318207 A1; Glaser et al., US Patent Publication No. 2009/0048122A1; Urech et al., WO 2008/110348 A1; Borras et al., WO 2009/000099 A2.Such modifications determined by covariance analysis can improvepotency, pharmacokinetic, pharmacodynamic, and/or manufacturabilitycharacteristics of an antigen binding protein.

Table 11 shows exemplary nucleic acid sequences encoding light and heavychain variable regions of anti-PAC1 receptor antibodies, and Table 12shows exemplary nucleic acid sequences encoding light and heavy chainvariable regions of anti-CGRP receptor antibodies. Polynucleotidesencoding the anti-PAC1 receptor and anti-CGRP receptor variable regionscan be used to construct the anti-PAC1 receptor and anti-CGRP receptorbinding domains, respectively, of the bispecific antigen bindingproteins described herein.

TABLE 11Exemplary Anti-PAC1 Receptor Variable Region Nucleic Acid Sequences SEQAntibody ID ID Designation Nucleic Acid Sequence NO:Light chain variable regions 01A, 01C, LV-01GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 464 01DGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGAGTTACAGTCCCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAA ACGT 01B LV-02GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 465GAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGAGTTACAGTCCCCCATTCACTTTCGGCGAGGGGACCAAAGTGGATATCA AACGT 02A, 02C LV-03GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 466GAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGAGTTACAGTCCCCCATTCACTTTCGGCCAGGGGACCAAAGTGGATATCA AACGT 03A, 03C, LV-04GATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAG 467 03DGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGCTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAATTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTA AGCGT 03B LV-05GATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAG 468GCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGCTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAATTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCGAGGGGACCAAGGTGGACATTA AGCGT 04A, 04C, LV-06GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCTGAGCCCGG 469 04DGTGAACGGGCGACCCTCAGCTGCCGAGCATCCCAGTCCGTCGGACGATCATTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCAGGGACCAAGGTGGACATTA AGCGT 04B LV-07GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCTGAGCCCGG 470GTGAACGGGCGACCCTCAGCTGCCGAGCATCCCAGTCCGTCGGACGATCATTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGAGAAGGGACCAAGGTGGACATTA AGCGT 05A, 05C, LV-08GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 471 05DGCGAGAGGGCCACCATCCACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTTCTTAACTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAACTTCTCATTTACCGGGCATCTACCCGGGAATCCGGGGTTCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTTCTGTCAGCAATATTATAGTGCTCCATTCACTTTCGGCCCTGG GACCAGAGTGGATATCAAACGT05B LV-09 GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 472GCGAGAGGGCCACCATCCACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTTCTTAACTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAACTTCTCATTTACCGGGCATCTACCCGGGAATCCGGGGTTCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTTCTGTCAGCAATATTATAGTGCTCCATTCACTTTCGGCGAGG GGACCAGAGTGGATATCAAACGT06A, 06C LV-10 GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 473GCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTTCTTAACTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAACTTCTCATTTACCGGGCATCTACCCGGGAATCCGGGGTTCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTTCTGTCAGCAATATTATAGTGCTCCATTCACTTTCGGCCCTGG GACCAGAGTGGATATCAAACGT06B LV-11 GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 474GCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTTCTTAACTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAACTTCTCATTTACCGGGCATCTACCCGGGAATCCGGGGTTCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTTCTGTCAGCAATATTATAGTGCTCCATTCACTTTCGGCGAGG GGACCAGAGTGGATATCAAACGT07 LV-12 GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAA 475AGGAGAAAGTCACCATCACCTGCCGGGCCAGTCAGAGCATTGGTAGTAGCTTACACTGGTACCAGCAGAAACCAGATCAGTCTCCAAAGCTCCTCATCAAGTATGCTTCCCAGTCCTTGTCAGGGATCCCCTCGAGGTTTAGTGGCAGTGGATCTGGGACACATTTCACCCTCACCATCAATAGCCTGGAAGCTGAAGATGCTGCAACGTATTACTGTCATCAGAGTAGTCGTTTACCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCA AACGAAC 08, 09, 10 LV-13GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAA 476AGGAGAAAGTCACCATCACCTGCCGGGCCAGTCAGAGCGTTGGTCGTAGTTTACACTGGTACCATCAGAAACCAGATCAGTCTCCAAAGCTCCTCATCAAGTATGCTTCCCAGTCCTTATCAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCCTCATTATCAATAGCCTGGAAGCTGAAGATGCTGCAACGTATTACTGTCATCAGAGTAGTCGTTTACCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCA AACGAA 11 LV-14GATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAG 477GCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCACCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGCTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAATTCACGCTTATCATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTA AGCGTAC 12, 13, 14 LV-15GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAA 478AGGAGAAAGTCACCATCACCTGCCGGGCCAGTCAGAGCGTTGGTCGTAGTTTACACTGGTACCAGCAGAAACCAGATCAGTCTCCAAAGCTCCTCATCAAGTATGCTTCCCAGTCCTTATCAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCCTCACTATCAATAGCCTGGAAGCTGAAGATGCTGCAACGTATTACTGTCATCAGAGTAGTCGTTTACCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCA AACGAAC 15, 16, 17, LV-16GAGATCGTACTTACTCAGTCACCCGGCACATTGTCCCTGAGCCCGG 479 18GTGAACGGGCGACCCTCAGCTGCCGAGCATCCCAGTCCGTCGGACGATCATTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGATCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCCGACTGGAACCCGAGGACTTCGCGACCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACAGGGGACCAAGGTGGAGATTA AGCGTA 19 LV-17GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAA 480AGGAGAAAGTCACCATCACCTGCCGGGCCAGTCAGAGCATTGGTCGTAGTTTACACTGGTACCAGCAGAAACCAGATCAGTCTCCAAAGCTCCTCTTCAAGTATGCTTCCCAGTCCTTATCAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCCTCACAATCAATAGCCTGGAAGCTGAAGATGCTGCAACGTATTACTGTCATCAGAGTAGTCGTTTACCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCA AACGAA 20 LV-18GATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAG 481GCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGTTCAAATACGCATCACAAAGCTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAATTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAA GCGTAC 21 LV-19GAAATTGTGTTGACGCAGTCGCCAGGCACCCTGTCTTTGTCTCCAG 482GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTAACAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGAGGTATGGTAGCTCACGGACGTTCGGCCAAGGGACCAAGGTGGAAA TCAAACGAA 22 LV-20GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTG 483GAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGCTCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGCAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAACTCTACAAACTCCATTCACTTTCGGCCCTGGGA CCAAAGTGGATATCAAACGT 23LV-21 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTG 484GAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGCTCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAACTCTACAAACTCCATTCACTTTCGGCCCTGGGA CCAAAGTGGATATCAAACGT 24LV-22 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAG 485GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTGTTAGCAGGAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCCGTGTTTTACTGTCAGCAGTTTGGTAGCTCACCGTGGACGTTCGGCCAAGGGACCAAGGTGGA AATCAAACGT 25 LV-23GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 486GCGAGAGGGCCACCATCCATTGCAAGTCCAGCCAGAATGTTTTATACAGCTCCAACAATAAGAACTTCTTAACTTGGTACCAGCAGAAACCAGGACAGCCCCCTAAACTGCTCATTTACCGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACGGATTTCACTCTCACTATCAGCAGTCTGCAGGCTGAAGATGTGGCAGTTTATTTCTGTCAGCAATATTATAGTGCTCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTAC 26 LV-24GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 487GCGAGAGGACCACCATCAAGTGCAAGTCCAGCCAGAGTGTTTTATACAGATCCAACAATAACAACTTCTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTATTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCTGTTTATTTCTGTCAGCAATATTATATTTCTCCGCTCACTTTCGGCGGAG GGACCAAGGTGGAGATCAAACGTA27 LV-25 GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 488GCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGTTCCAACAATAAGCACTACTTAGCTTGGTACCGGCAGAAACCAGGACAGCCTCCTAAACTGCTCATTTACAGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTGGCAGTGTATTACTGTCAGCAATATTATAGTTCTCCATTCACTTTCGGCCCTG GGACCAAAGTGGATATCAAACGTA28 LV-26 GACATCGTGATGACTCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 489GCGAGAGGGCCACCATCCACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAGGAACTTCTTAAGTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAACTGCTCATTTACCGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTTCTGTCAGCAATATTATAGTGCTCCATTCACTTTCGGCCCTGGGACCACAGTGGATATCAAACGTAC 29 LV-27GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 490GCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGTTCCAACAATAAGAACTACTTAGCTTGGTACCGGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACAGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTGTATCACTGTCAGCAATATTATAGTTCTCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTAC Heavy chain variable regions 01A, 01C, HV-01CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCG 491 01D, 02A,CAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTA 02CGCAACAGTGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATATTACAGGTCCAAGTGGTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCTATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTC TCTAGT 01B HV-02CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCG 492CAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAAAGCTTGAGTGGCTGGGAAGGACATATTACAGGTCCAAGTGGTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCTATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTC TCTAGT 03A, 03C, HV-03CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGA 493 03D, 09,GCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCC 13, 15GCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGT 03B HV-04CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGA 494GCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGAAGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGT 04A, 04C, HV-05CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 495 04DAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGT 04B HV-06CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 496AGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGAAGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGT 05A, 05C, HV-07CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCA 497 05DCAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAACACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGGAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 05B HV-08CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCA 498CAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGAAGCTGGAGTGGATTGGGTACATCTATTACAGTGGGAACACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGGAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 06A, 06C HV-09CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCA 499GAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAACACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGTGGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 06B HV-10CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCA 500GAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGAAGCTGGAGTGGATTGGGTACATCTATTACAGTGGGAACACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTACGAGAGGAGGAGCAGCTCGCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 07 HV-11CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 501AGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTTACTATGCCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTGGCAGTTATCTCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGGATACGATCTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG 11, 14 HV-12CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 502AGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCGGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGAATCTGCTAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGC 08, 12 HV-13CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 503AGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGAATCTGCTAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGC 10 HV-14CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 504AGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCGGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGAATCTGCTAATGGACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 16 HV-15CAAGTTCAGTTGGTGCAATCTGGAGCCGAAGTAAAGAAGCCAGGA 505GCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACAGCCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGT 17 HV-16CAAGTTCAGTTGGTGCAATCTGGAGCCGAAGTAAAGAAGCCAGGA 506GCTTCAGTGAAAGTCTCTTGTGCCGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACAACTCAAAAAATACAGCCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGT 18 HV-17GAGGTGCAGCTGCTGGAGTCTGGGGGAGGCCTGGTCCAGCCTGGG 507GGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGC 19, 20 HV-18CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 508AGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCGCTATGCCATGCACTGGGTCCGCCAGGCTTCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCTAATGAGCAGCCTGAGAGCTGAGGACACGGCTGTGTTTTACTGTGCGAGAGGATACGATATTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 21 HV-19CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGG 509GCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACGCTTACAATGGTCACACAAACTATGCACAGACGTTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGGGAACTGGAACTACGCTCCTTCTATTACTTCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCCCCGT CTCTAGTG 22 HV-20CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGTCTGGG 510GCCTCTTTGAAGGTCTCCTGCAAGGCTTCTGGTTACATTTTTACCCGCTATGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCACCACTTACAATGGTAACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCATAGACACATCCACGAGCACAGCCTACATGGAACTGAGAAGCCTCAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAAGAGTGCGGTATAGTGGGGGCTACTCGTTTGACAACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT 23 HV-21CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGTCTGGG 511GCCTCTTTGAAGGTCTCCTGCAAGGCTTCTGGTTACATTTTTACCCGCTATGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCACCACTTACAATGGTAATACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAACTGAGGAGCCTCAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAAGAGTGCGGTACAGTGGGGGCTACTCGTTTGACAACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GTGC 24 HV-22CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCG 512GAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTACTACTGGAGCTGGATCCGGCAGCCCGCCGGGAAGGGACTGGAATGGATTGGGCGTATCTATACCAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATGTCAATAGGCACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGATTATTGCATCTCGTGGCTGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACCGTCTCTAGTG 25, 28 HV-23CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCA 513CAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAACACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGGAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGGAGGAGCAGCTCGCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGTGC 26 HV-24CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCG 514CAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAGGTGGTATAATGATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGGGTCTTTTATAGCAAAGGTGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGT CTCTAGTG 27 HV-25CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCA 515CAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCCGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATATATTACAGTGGGAATACCTACTACAACCCGTCCCTCAAGAGTCGAGTTATCATATCAGGAGACACGTCTAAGAACCAGCTCTCCCTGAAGCTGAGGTCTGTGACTGCCGCGGACACGGCCGTGTATTATTGTGCGAGAGGAGGAGCAGCTCGCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGTGC 29 HV-26CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCA 516CAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTTCTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAATACCTACTACAACCCGTCCCTCAAGAGTCGAGTTATCATATCAGGAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACGGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGGAGGAGCAGCTCGCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGTGC

TABLE 12Exemplary Anti-CGRP Receptor Variable Region Nucleic Acid Sequences SEQAntibody ID ID Designation Nucleic Acid Sequence NO:Light chain variable regions 50A, 50C, LV-101CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGC 517 50D, 70AGAGAGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGCAGTAATTATGTATACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAAACTCCTCATCTTTAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGCTTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGAGGGACCAAG CTGACCGTCCTAGGT 50B LV-102CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGC 518AGAGAGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGCAGTAATTATGTATACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAAACTCCTCATCTTTAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGCTTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCAAGGGGACCAAG CTGACCGTCCTAGGT 51A, 51C,LV-103 CAGTCTGTGCTGACTCAGTCACCCTCAGCGTCTGGGACCCCCGGGC 519 51DAGAGAGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGCAGTAATTATGTATACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAAACTCCTCATCCTTAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGACCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGACTATTATTGTGCAGCATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGAGGGACCAAG CTGACCGTCCTAGGT 51B LV-104CAGTCTGTGCTGACTCAGTCACCCTCAGCGTCTGGGACCCCCGGGC 520AGAGAGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGCAGTAATTATGTATACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAAACTCCTCATCCTTAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGACCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGACTATTATTGTGCAGCATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCAAGGGGACCAAG CTGACCGTCCTAGGT 52A, 52C,LV-105 CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGAC 521 52D, 53A,AGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGA 53CATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAG CTGACCGTCCTAGGT 52B, 53BLV-106 CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGAC 522AGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCAAGGGGACCAAG CTGACCGTCCTAGGT 54A, 54C,LV-107 CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGAC 523 56A, 56C,AGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGA 71ATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAG CTGACCGTCCTAGGT 54B, 56BLV-108 CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGAC 524AGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCAAGGGGACCAAG CTGACCGTCCTAGGT 55A, 55CLV-109 CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGAC 525AGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAG CTGACCGTCCTAGGT 55B LV-110CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGAC 526AGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCAAGGGGACCAAG CTGACCGTCCTAGGT 57A, 57C,LV-111 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAG 527 57D, 58A,GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCA 58CGCGGCTACTTAACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACGGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAACTCACTGAGCAGGTTTGGCCAGGGGACCAAGCTGGA AATCAAACGT 57B, 58B LV-112GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAG 528GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCGGCTACTTAACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGTACGGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAACTCACTGAGCAGGTTTGGCAAGGGGACCAAGCTGGA GATCAAACGT 59 LV-113CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGAGGCCCCAGGA 529CAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAA GCTGACCGTCCTA 60 LV-114CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGC 530AGAGAGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGCAGTAATTATGTATACTGGTACCAGCAGCTCCCAGGAGCGGCCCCCAAACTCCTCATCTTTAGGAGTAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGAGGGACCAAG CTGACCGTCCTA 61 LV-115GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 531GAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTTTCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTAGCAACTTATTACTGTCTACAGTATAATATTTACCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATC AAA 62 LV-116TCTTCTGAGCTGACTCAGGACCCTACTGTGTCTGTGGCCTTGGGAC 532AGACAGTCAAAATCACATGCCAAGGAGACAGCCTCAGAAGTTTTTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCTTCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTATTGTAATTCCCGGGACAGCAGTGTTTACCATCTGGTACTCGGCGGAGGGACCAAGCTGAC CGTCCTA 63 LV-117GATATTATACTGGCCCAGACTCCACTTTCTCTGTCCGTCACCCCTG 533GACAGCCGGCCTCCATCTCCTGCAAGTCTAGTCAGAGCCTCCTGCACAGTGCTGGAAAGACCTATTTGTATTGGTACCTGCAGAAGCCAGGCCAGCCTCCACAGCTCCTGATCTATGAAGTTTCCAACCGGTTCTCTGGAGTGCCAGATAGGTTCAGTGGCAGCGGGTCAGGGACAGATTTCACACTGAAAATCAGCCGGGTGGAGGCTGAGGATGTTGGGATTTATTACTGCATGCAAAGTTTTCCGCTTCCGCTCACTTTCGGCGGAGGGA CCAAGGTGGAGATCAAA 64LV-118 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTG 534GAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTTTTGGGTACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACTCCATTCACTTTCGGCCCTGGGAC CAAAGTGGATATCAAA 65LV-119 GATATTATTCTGACCCAGACTCCACTTTCTCTGTCCGTCACCCCTG 535GACAGCCGGCCTCCATCTCCTGCAAGTCTAGTCAGAGCCTCCTGCACAGTGATGGAAAGACCTATTTGTATTGGTACCTGCAGAAGCCCGGCCAGCCTCCACAGCTCCTGATCTATGAAGTTTCCAACCGGTTCTCTGGAGAGCCAGATAGGTTCAGTGGCAGCGGGTCAGGGACAGATTTCACACTGAAAATCAGCCGGGTGGAGGCTGAGGATGTTGGGACTTATTATTGCATGCAAAGTTTTCCGCTTCCGCTCACTTTCGGCGGAGGGA CCAAGGTGGAGATCAAA 66LV-120 CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGAC 536AGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGTTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAG CTGACCGTCCTA 67 LV-121CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGC 537AGAGGGTCACCATCTCTTGTTCTGGAAGCAGTTCCAATATCGGAAGTAATACTGTGAACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCTATACTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGACTCCAGTCTGAGGATGAGGCTGATTTTTACTGTGCAGCGCGGGATGAGAGCCTGAATGGTGTGGTATTCGGCGGAGGGACCAAGC TGACCGTCCTA 68 LV-122GATATTACACTGACCCAGACTCCACTTTCTCTGTCCGTCTCCCCTG 538GACAGCCGGCCTCCATCTCCTGCAAGTCTAGTCAGAGCCTCCTGCACAGTGATGGAAGGAACTATCTGTATTGGTACCTGCAGAAGCCAGGCCAGCCTCCACAGCTCCTGATCTATGAAGTGTCCAACCGGTTCTCTGGACTGCCAGATAGGTTCAGTGGCAGCGGGTCAGGGACAGATTTCACACTGAAAATCAGCCGGGTGGAGGCTGAGGATGTTGGGATTTATTACTGCATGCAAAGTTTTCCGCTTCCGCTCACTTTCGGCGGAGGGA CCAAGGTGGAGATCAAA 69LV-123 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 539GAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAAGGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGGAGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGTATAATAGTTTCCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAAHeavy chain variable regions 50A, 50C, HV-101GAGGTACAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGG 540 50DGGGTCCCTCAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCGGTAACGCCTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGTGGGACAACAGACTACGCTGCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTTCTGTACCACAGATCGGACCGGGTATAGCATCAGCTGGTCTAGTTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGAACAACAGTTACCGTCTCTAGT 50B HV-102GAGGTACAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGG 541GGGTCCCTCAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCGGTAACGCCTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGAGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGTGGGACAACAGACTACGCTGCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTTCTGTACCACAGATCGGACCGGGTATAGCATCAGCTGGTCTAGTTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGAACAACAGTTACCGTCTCTAGT 51A, 51C, HV-103GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGG 542 51DGGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAACGCCTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGTGGGACAACAGACTACACTGCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTGCAAATGAATAGCCTGAAAGCCGAGGACACAGCCGTGTATTACTGTACCACAGATCGGACCGGGTATAGCATCAGCTGGTCTAGTTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGAACAACAGTTACCGTCTCTAGT 51B HV-104GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGG 543GGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAACGCCTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGAGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGTGGGACAACAGACTACACTGCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTGCAAATGAATAGCCTGAAAGCCGAGGACACAGCCGTGTATTACTGTACCACAGATCGGACCGGGTATAGCATCAGCTGGTCTAGTTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGAACAACAGTTACCGTCTCTAGT 52A, 52C, HV-105CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGG 544 52D, 54A,AGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTA 54C, 55A,GCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGG 55C, 59,AGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGT 66AGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGT 52B, 54B, HV-106CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGG 545 55BAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGT 53A, 53C, HV-107CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGG 546 56A, 56CAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAGAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGT 53B, 56B HV-108CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGG 547AGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAGAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGT 57A, 57C, HV-109CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 548 57DAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCATCATCTCCAGAGATAAATCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAGCAGCAGCTGGCCTCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACAA CAGTTACCGTCTCTAGT 57BHV-110 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 549AGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCATCATCTCCAGAGATAAATCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAGCAGCAGCTGGCCTCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACAA CAGTTACCGTCTCTAGT 58A, 58CHV-111 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 550AGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGAGTCCGTGAAGGGCCGATTCATCATCTCCAGAGATAAATCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAGCAGCAGCTGGCCTCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACAA CAGTTACCGTCTCTAGT 58BHV-112 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 551AGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGGAAGGAGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGAGTCCGTGAAGGGCCGATTCATCATCTCCAGAGATAAATCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGCGGGGGGTATAGCAGCAGCTGGCCTCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACAA CAGTTACCGTCTCTAGT 60HV-113 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGG 552GGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAACGCCTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTATTAAAAGCACAACTGATGGTGGGACAACAGACTACGCTGCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTACCACAGATCGGACCGGATATAGCATCAGCTGGTCTAGTTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 61 HV-114GAGGTGCAGCTATTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGG 553GAGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTCGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAATAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGATCAAAGGGAGGTAGGGCCGTATAGCAGTGGCTGGTACGACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 62 HV-115CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGG 554GCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTTCTGTGCGAGAGATCAAATGAGTATTATTATGCTTCGGGGAGTTTTTCCCCCTTACTATTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 63, 65, 68 HV-116CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGG 555AGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTCATATGATGGAAGTCATGAATCCTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTTCTGTGCGAGAGAGAGGAAACGGGTTACGATGTCTACCTTATATTACTACTTCTACTACGGTATGGACGTCTGGGGCCAA GGGACCACGGTCACCGTCTCTAGT64 HV-117 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCAGGG 556CGGTCCCTGAGACTCTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATAGGTTTCATTAGAAGCAGAGCTTATGGTGGGACACCAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAACCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTTCTGTGCTAGAGGACGGGGTATTGCAGCTCGTTGGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT 67 HV-118CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGG 557GCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTACTATATGTACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCCCTAATAGTGGTGGCACAAACTATGCCCAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCTATCAGCACAGCCTACATGGAGCTGAGTAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGTGAGAGGAGGATATAGTGGCTACGCTGGGCTCTACTCCCACTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCTAGT 69HV-119 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGG 558GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATACACCTTCAGTACCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTAGTTACAGATATTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAGTAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGAAGGGGTGTCTGGCAGTTCGCCGTATAGCATCAGCTGGTACGACTACTATTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 70 HV-120GAGGTACAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGG 559GGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCGGTAACGCCTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGTGGGACAACAGACTACGCTGCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTACCACAGATCGGACCGGGTATAGCATCAGCTGGTCTAGTTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT 71 HV-121CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGG 560AGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCATTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTACTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTCTGGCCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGT

Isolated nucleic acids encoding anti-PAC1 receptor binding domains ofthe bispecific antigen binding proteins of the invention may comprise anucleotide sequence that is at least 80% identical, at least 90%identical, at least 95% identical, or at least 98% identical to any ofthe nucleotide sequences listed in Table 11. In some embodiments, anisolated nucleic acid encoding an anti-PAC1 receptor light chainvariable region comprises a sequence selected from SEQ ID NOs: 464 to490. In related embodiments, an isolated nucleic acid encoding ananti-PAC1 receptor heavy chain variable region comprises a sequenceselected from SEQ ID NOs: 491 to 516. Isolated nucleic acids encodinganti-CGRP receptor binding domains of the bispecific antigen bindingproteins of the invention may comprise a nucleotide sequence that is atleast 80% identical, at least 90% identical, at least 95% identical, orat least 98% identical to any of the nucleotide sequences listed inTable 12. In some embodiments, an isolated nucleic acid encoding ananti-CGRP receptor light chain variable region comprises a sequenceselected from SEQ ID NOs: 517 to 539. In related embodiments, anisolated nucleic acid encoding an anti-CGRP receptor heavy chainvariable region comprises a sequence selected from SEQ ID NOs: 540 to560.

In embodiments in which the bispecific antigen binding protein of theinvention is a heterodimeric antibody, the isolated nucleic acidencoding an anti-PAC1 receptor antibody light chain may comprise anucleotide sequence that is at least 80% identical, at least 90%identical, at least 95% identical, or at least 98% identical to any ofthe nucleotide sequences listed in Table 6A. In certain embodiments, theisolated nucleic acid encoding an anti-PAC1 receptor light chain of aheterodimeric antibody of the invention comprises a sequence selectedfrom SEQ ID NOs: 222 to 232. In these and other embodiments, theisolated nucleic acid encoding an anti-PAC1 receptor antibody heavychain may comprise a nucleotide sequence that is at least 80% identical,at least 90% identical, at least 95% identical, or at least 98%identical to any of the nucleotide sequences listed in Table 6B. In someembodiments, the isolated nucleic acid encoding an anti-PAC1 receptorheavy chain of a heterodimeric antibody of the invention comprises asequence selected from SEQ ID NOs: 252 to 270.

In other embodiments in which the bispecific antigen binding protein ofthe invention is a heterodimeric antibody, the isolated nucleic acidencoding an anti-CGRP receptor antibody light chain may comprise anucleotide sequence that is at least 80% identical, at least 90%identical, at least 95% identical, or at least 98% identical to any ofthe nucleotide sequences listed in Table 7A. In certain embodiments, theisolated nucleic acid encoding an anti-CGRP receptor light chain of aheterodimeric antibody of the invention comprises a sequence selectedfrom SEQ ID NOs: 283 to 294. In these and other embodiments, theisolated nucleic acid encoding an anti-CGRP receptor antibody heavychain may comprise a nucleotide sequence that is at least 80% identical,at least 90% identical, at least 95% identical, or at least 98%identical to any of the nucleotide sequences listed in Table 7B. In someembodiments, the isolated nucleic acid encoding an anti-CGRP receptorheavy chain of a heterodimeric antibody of the invention comprises asequence selected from SEQ ID NOs: 317 to 338.

Nucleic acid sequences encoding the light chains and modified heavychains (e.g., fusion proteins comprising a heavy chain and a scFv) ofexemplary bispecific antigen binding proteins of the invention in theIgG-scFv format are listed in Table 13. In such embodiments, theisolated nucleic acid encoding the light chain of the IgG-scFv moleculesmay comprise a nucleotide sequence that is at least 80% identical, atleast 90% identical, at least 95% identical, or at least 98% identicalto any of the light chain nucleotide sequences listed in Table 13. Forinstance, in some embodiments, the isolated nucleic acid encoding thelight chain of the IgG-scFv molecules comprises a sequence selected fromSEQ ID NOs: 561 to 564. In related embodiments, the isolated nucleicacid encoding the modified heavy chain of the IgG-scFv molecules maycomprise a nucleotide sequence that is at least 80% identical, at least90% identical, at least 95% identical, or at least 98% identical to anyof the modified heavy chain nucleotide sequences listed in Table 13. Incertain embodiments, the isolated nucleic acid encoding the modifiedheavy chain of the IgG-scFv molecules comprises a sequence selected fromSEQ ID NOs: 565 to 594.

TABLE 13 Nucleic Acid Sequences of Exemplary Bispecific Antigen BindingProteins in the IgG-scFv Format IgG-scFv Light Chain MoleculeNucleic Acid Modified Heavy Chain Designation SequenceNucleic Acid Sequence Anti-PAC1 Receptor IgG x Anti-CGRP Receptor scFviPS:386738 GATATCCAGCTCAC CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCTCAATCGCCATCAT AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCA TTCTCTCCGCTTCGCGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCG GTAGGCGACCGGGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGG TCACGATCACATGCGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCAC AGGGCGTCGCAAAAATGACACGGGACACCTCAACCAGTACACTCTATATGGAAC GCATTGGGAGGTCGTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCG TTGCATTGGTATCACTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGG GCAGAAACCCGGAGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAG AAGGCCCCGAAACGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC TTCTGATCAAATACTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTA GCATCACAAAGCTTCTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GAGCGGTGTGCCGTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC CGCGCTTCTCCGGTAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG TCCGGAAGCGGAACAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACA CGGAATTCACGCTTAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAA ACAATCTCCTCACTATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACC GCAGCCCGAGGATTTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA TCGCGACCTATTACACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA TGTCACCAGTCATCCATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC CAGACTCCCGTTTAAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGC CTTTTGGCCCTGGGCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACC ACCAAGGTGGACAGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA TTAAGCGTACGGTGATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC GCTGCACCATCTGTCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA CATCTGATGAGCAGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTC TTGAAATCTGGAACAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG TGCCTCTGTTGTGTCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG GCCTGCTGAATAACTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA TTCTATCCCAGAGACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCA GGCCAAAGTACAGTGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCA TGGAAGGTGGATAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAG ACGCCCTCCAATCGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGC GGTAACTCCCAGGAGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCC GAGTGTCACAGAGTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGC CAGGACAGCAAGGCAGGCTCCAGGCAAGTGTCTGGAGTGGGTGGCAGTTATATC ACAGCACCTACAGCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGG CTCAGCAGCACCCTCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT GACGCTGAGCAAATCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGT GCAGACTACGAGAATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTG AACACAAAGTCTACGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCC GCCTGCGAAGTCACAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCT CCATCAGGGCCTGAGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTG GCTCGCCCGTCACAACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGT AAGAGCTTCAACACACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAA GGGGAGAGTGTTTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAA (SEQ ID ACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCC NO: 561)TGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCG GCTGTGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 565) iPS:386764 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTGCTTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGG GCCAAGGGACAACAGTTACTGTCTCTAGT(SEQ ID NO: 566) iPS:386762 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTGCTTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGG GCCAAGGGACAACAGTTACTGTCTCTAGT(SEQ ID NO: 567) iPS:386760 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTGCTTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGG GCCAAGGGACAACAGTTACTGTCTCTAGT(SEQ ID NO: 568) iPS:386758 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTGCTTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGG GCCAAGGGACAACAGTTACTGTCTCTAGT(SEQ ID NO: 569) iPS:386756 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTGCTTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGG GCCAAGGGACAACAGTTACTGTCTCTAGT(SEQ ID NO: 570) iPS:386754 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTC GGCGGAGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 571) iPS:386752 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCG GCGGAGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 572) iPS:386750 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGTGTCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCG GCTGTGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 573) iPS:386748 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTC GGCGGAGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 574) iPS:386746 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCG GCGGAGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 575) iPS:386744 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGTGTCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCG GCTGTGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 576) iPS:386742 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGTGTCTGGAGTGGGTGGCAGTTATATCCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTC GGCTGTGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 577) iPS:386740 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGTGTCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTC GGCTGTGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 578) iPS:386736 SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC NO: 561AGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACTGTCTCTAGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGGTTTTCG GCGGAGGGACCAAGCTGACCGTGCTA(SEQ ID NO: 579) Anti-CGRP Receptor IgG x Anti-PAC1 Receptor scFviPS:386731 CAGTCTGTGTTGAC CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCGCAGCCGCCCTCAG TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAC TGTCTGCGGCCCCACTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGG GGACAGAAGGTCACAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAA CCATCTCCTGCTCTGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCA GGAAGCAGCTCCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATG ACATTGGGAATAATAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGC TATGTATCCTGGTAGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCA CCAGCAGCTCCCAGCTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAA GAACAGCCCCCAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCT ACTCCTCATTTATGTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG ACAATAATAAGCGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG ACCCTCAGGGATTCGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT CTGACCGATTCTCTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTC GGCTCCAAGTCTGGCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA CACGTCAACCACCCCCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC TGGGCATCACCGGAACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA CTCCAGACTGGGGAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGG CGAGGCCGATTATTGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA ACTGCGGAACATGCCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGG GGATAGCCGCCTGATGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG GTGCTGTGGTTTTCTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GGCGGAGGGACCAGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG AGCTGACCGTCCTATCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG GGTCAGCCCAAGGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCAT CCAACCCCACTGTCCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC ACTCTGTTCCCGCCCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC CTCCTCTGAGGAGCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA TCCAAGCCAACAATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC GGCCACACTAGTGTCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCC GTCTGATCAGTGACGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAG TTCTACCCGGGAGCAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT TGTGACAGTGGCCTGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAA GGAAGGCAGATGGGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCC CAGCCCCGTCAAGGGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCG CGGGAGTGGAGACGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAG CACCAAACCCTCCACATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAA AACAGAGCAACAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTG CAAGTACGCGGCCAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAAC AGCAGCTACCTGAGGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTT CCTGACGCCCGAGCCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTAC AGTGGAAGTCCCACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTGGAGGCG AGAAGCTACAGCTGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAA GCCAGGTCACGCATGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGG GAAGGGAGCACCGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTT TGGAGAAGACAGTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCA GGCCCCTACAGAATGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCA GTTCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATG (SEQ ID ACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCT NO: 562)AGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGC AGGGGACACTCGTAACCGTGTCTTCA(SEQ ID NO: 580) iPS:386725 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 562TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGC AGGGGACACTCGTAACCGTGTCTTCA(SEQ ID NO: 581) iPS:386717 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 562TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGTGCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCT GTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 582) iPS:386715 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 562TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGTGCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCT GTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 583) iPS:386707 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 562TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCC CTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 584) iPS:386705 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 562TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCC CTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 585) iPS:386723 CAGTCTGTGTTGACCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC GCAGCCGCCCTCAGTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAC TGTCTGCGGCCCCACTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGG GGACAGAAGGTCACAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAA CCATCTCCTGCTCTGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCA GGAAGCAGCTCCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATG ACATTGGGAATAATAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGC TATGTATCCTGGTAGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCA CCAGCAGCTCCCAGCTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAA GAACAGCCCCCAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCT ACTCCTCATTTATGTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG ACAATAATAAGCGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG ACCCTCAGGGATTCGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT CTGACCGATTCTCTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTC GGCTCCAAGTCTGGCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA CACGTCAGCCACCCCCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC TGGGCATCACCGGAACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA CTCCAGACTGGGGAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGG CGAGGCCGATTATTGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA ACTGCGGAACATGCCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGG GGATAGCCGCCTGATGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG GTGCTGTGGTTTTCTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GGCGGAGGGACCAGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG AGCTGACCGTCCTATCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG GGTCAGCCCAAGGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCAT CCAACCCCACTGTCCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC ACTCTGTTCCCGCCCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC CTCCTCTGAGGAGCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA TCCAAGCCAACAATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC GGCCACACTAGTGTCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCC GTCTGATCAGTGACGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAG TTCTACCCGGGAGCAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT TGTGACAGTGGCCTGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAA GGAAGGCAGATGGGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCC CAGCCCCGTCAAGGCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC CGGGAGTGGAGACAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCA CACCAAACCCTCCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCG AACAGAGCAACAAGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGG CAAGTACGCGGCCGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCAC AGCAGCTACCTGAGAATGACACGGGACACCTCAACCAGTACACTCTATATGGAAC CCTGACGCCCGAGCTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCG AGTGGAAGTCCCACCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGG AGAAGCTACAGCTGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGA GCCAGGTCACGCATTCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCA GAAGGGAGCACCGGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGA TGGAGAAGACAGTCCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGA GGCCCCTACAGAATGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGTGCCCG GTTCAAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGT (SEQ ID GCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCA NO: 563)CGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCT GTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 586) iPS:386719 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 563TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGTGCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCT GTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 587) iPS:386713 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 563TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCC CTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 588) iPS:386709 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 563TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCC CTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 589) iPS:386727 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 563TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGC AGGGGACACTCGTAACCGTGTCTTCA(SEQ ID NO: 590) iPS:386721 CAGTCTGTGTTGACCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC GCAGCCGCCCTCAGTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAC TGTCTGCGGCCCCACTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGG GGACAGAAGGTCACAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAA CCATCTCCTGCTCTGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCA GGAAGCAGCTCCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATG ACATTGGGAATAATAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGC TATGTATCCTGGTAGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCA CCAGCAGCTCCCAGCTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAA GAACAGCCCCCAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCT ACTCCTCATTTATGTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG ACAATAATAAGCGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG ACCCTCAGGGATTCGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT CTGACCGATTCTCTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTC GGCTCCAAGTCTGGCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA CACGTCAGCCACCCCCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC TGGCCATCACCGGAACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA CTCCAGACTGGGGAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGG CGAGGCCGATTATTGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA ACTGCGGAACATGCCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGG GGATAGCCGCCTGATGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG GTGCTGTGGTTTTCTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GGCGGAGGGACCAGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCG AGCTGACCGTCCTATCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG GGTCAGCCCAAGGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCAT CCAACCCCACTGTCCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC ACTCTGTTCCCGCCCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC CTCCTCTGAGGAGCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA TCCAAGCCAACAATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC GGCCACACTAGTGTCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCC GTCTGATCAGTGACGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAG TTCTACCCGGGAGCAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT TGTGACAGTGGCCTGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAA GGAAGGCAGATGGGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCC CAGCCCCGTCAAGGCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCC CGGGAGTGGAGACAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCA CACCAAACCCTCCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCG AACAGAGCAACAAGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGG CAAGTACGCGGCCGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCAC AGCAGCTACCTGAGAATGACACGGGACACCTCAACCAGTACACTCTATATGGAAC CCTGACGCCCGAGCTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCG AGTGGAAGTCCCACCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGG AGAAGCTACAGCTGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGA GCCAGGTCACGCATTCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCA GAAGGGAGCACCGGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGA TGGAGAAGACAGTCCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGA GGCCCCTACAGAATGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGTGCCCG GTTCAAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGT (SEQ IDGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCA NO: 564)CGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCT GTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 591) iPS:386711 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 564TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCCTCAGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCC CTGGGACCAAGGTGGACATTAAGCGT(SEQ ID NO: 592) iPS:386733 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 564TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGC AGGGGACACTCGTAACCGTGTCTTCA(SEQ ID NO: 593) iPS:386729 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCC NO: 564TGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATTAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTTTCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATTACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTGGAGGCGGAGGATCTGGTGGCGGTGGTTCTGGCGGCGGAGGCTCCCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGC AGGGGACACTCGTAACCGTGTCTTCA(SEQ ID NO: 594)

Nucleic acid sequences encoding the three components (e.g., lightchains, modified heavy chains, and second polypeptides comprising theother half of the carboxyl-terminal Fab domains) of exemplary bispecificantigen binding proteins of the invention in the IgG-Fab format arelisted in Table 14. In such embodiments, the isolated nucleic acidencoding the light chain of the IgG-Fab molecules may comprise anucleotide sequence that is at least 80% identical, at least 90%identical, at least 95% identical, or at least 98% identical to any ofthe light chain nucleotide sequences listed in Table 14. For instance,in some embodiments, the isolated nucleic acid encoding the light chainof the IgG-Fab molecules comprises a sequence selected from SEQ ID NOs:225, 287, 595, and 596. In related embodiments, the isolated nucleicacid encoding the modified heavy chain of the IgG-Fab molecules maycomprise a nucleotide sequence that is at least 80% identical, at least90% identical, at least 95% identical, or at least 98% identical to anyof the modified heavy chain nucleotide sequences listed in Table 14. Incertain embodiments, the isolated nucleic acid encoding the modifiedheavy chain of the IgG-Fab molecules comprises a sequence selected fromSEQ ID NOs: 597 to 620. In these and other embodiments, the isolatednucleic acid encoding the second polypeptide of the IgG-Fab molecules,which comprises the other half of the carboxyl-terminal Fab domain (e.g.a Fd fragment or second light chain), may comprise a nucleotide sequencethat is at least 80% identical, at least 90% identical, at least 95%identical, or at least 98% identical to any of the second polypeptidenucleotide sequences listed in Table 14. In some embodiments, theisolated nucleic acid encoding the second polypeptide of the IgG-Fabmolecules comprises a sequence selected from SEQ ID NOs: 621 to 632.

TABLE 14Nucleic Acid Sequences of Exemplary Bispecific Antigen Binding Proteins in theIgG-Fab Format Second  IgG-Fab Light Chain Polypeptide MoleculeNucleic Acid Modified Heavy Chain Nucleic Acid Designation SequenceNucleic Acid Sequence SequenceAnti-PAC1 Receptor IgG x Anti-CGRP Receptor Fab iPS:392513 GATATCCAGCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG CAGGTGCAGCTG CTCACTCAATAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA GTGGAATCTGGG TCGCCATCAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC GGAGGCGTGGTC TTTCTCTCCGATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGA CAGCCTGGGAGG CTTCGGTAGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT TCCCTGAGACTCT GCGACCGGGAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA CCTGTGCAGCCTC TCACGATCACAATGACACGGGACACCTCAACCAGTACACTCTA TGGATTCACCTTC CATGCAGGGTATGGAACTGTCTAGCCTGAGATCCGAGGACACC AGTAGCTTTGGC CGTCGCAAAGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT ATGCACTGGGTC GCATTGGGAGACGGGTTATCCTGATTACTGGGGGCAGGGGACA CGCCAGGCTCCA GGTCGTTGCCTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC GGCAAGGGGCTG ATTGGTATCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA GAGTGGGTGGCA AGCAGAAACCCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT GTTATATCATTTG CCGGAAAGGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG ATGGAAGTATTA CCCCGAAACTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA AGTATTCTGTAGA TTCTGATCACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC CTCCGTGAAGGG AATACGCATTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CCGATTCACCATC CACAAAGCTGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCCAGAGACAAT TGAGCGGTGTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TCAAAGAACACG TGCCGTCGCAGTTGAGCCCAAATCTTGTGACAAAACTCACACA CTGTTTCTGCAAA GCTTCTCCGTGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG TGAACAGCCTGC GTTCCGGAAGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GAGCCGAGGACA GCGGAACGGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CGGCTGTGTATTA AATTCACGCCATGCGTGGTGGTGGACGTGAGCCACGAAGACCC CTGTGCGAGAGA TTACAATCTTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG TCGGCTCAATTAC CCTCACTGCGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG TATGATAGTAGT AGCCCGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT GGTTATTATCACT ATTTCGCGACCTCACCGTCCTGCACCAGGACTGGCTGAATGGC ACAAATACTACG CCTATTACTAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTATGGCCGTCTG GTCACCAGTTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC GGGCCAAGGAAC CATCCAGACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC AACAGTTACCGT TCCCGTTTACCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC CTCTAGTGGTCAG TTTTGGCCCTAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA CCCAAGGCCAAC GGGACCAAGTCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT CCCACTGTCACTC GTGGACATTGGGCAGCCGGAGAACAACTACAAGACCACGCCTC TGTTCCCGCCCTC AAGCGTACGCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT CTCTGAGGAGCT GTGGCTGCAAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CCAAGCCAACAA CCATCTGTCTCAGGGGAACGTCTTCTCATGCTCCGTGATGCATG GGCCACACTAGT TCATCTTCCCAGGCTCTGCACAACCACTACACGCAGAAGAGCCT GTGTCTGATCAGT GCCATCTGAAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT GACTTCTACCCGG TGAGCAGTTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT GAGCTGTGACAG GAAATCTGGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT TGGCCTGGAAGG AACTGCCTCCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT CAGATGGCAGCC TGTTGTGTGAATTATGTATCCTGGTACCAGCAGCTCCCAGGAA CCGTCAAGGCGG CCTGCTGAACAGCCCCCAAACTCCTCATTTATGACAATAATAA GAGTGGAGACCA TAACTTCTATGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT CCAAACCCTCCA CCCAGAGAGCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC AACAGAGCAACA GCCAAAGTACGGACTCCAGACTGGGGACGAGGCCGATTATTAC ACAAGTACGCGG CAGTGGAAGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG CCGAAAGCTACC GTGGATAACTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGC TGAGCCTGACGC GCCCTCCAATAGTACAAAGGGCCCCTCCGTCTTTCCACTCGCAC CCGAGCAGTGGA TCGGGTAACCCAGTTCAAAGTCCACTTCTGGAGGCACTGCGGC AGTCCCACAGAA TCCCAGGAGCTTGGGCTGTTTGGTGAAAGACTACTTCCCAGAG GCTACAGCTGCC AGTGTCACACCAGTGACAGTCTCTTGGAATAGCGGAGCACTGA AGGTCACGCATG GAGCAGGACCCAGCGGTGTGCATACCTTTCCAGCTGTGCTGCAG AAGGGAGCACCG AGCAAGGACAGCAGCGGCCTCTACTCACTGAAGAGTGTCGTCA TGGAGAAGACAG AGCACCTACCCGTTCCCTCTTCCAGCCTCGGCACTCAAACTTAC TGGCCCCTACAG AGCCTCGAGATCTGCAACGTGAATCATAAGCCATCTAACACCA AATGTTCA AGCACCCTG AGGTAGACAAGAAAGTC(SEQ ID ACGCTGAGC (SEQ ID NO: 597) NO: 621) AAAGCAGAC TACGAGAAACACAAAGTC TACGCCTGC GAAGTCACC CATCAGGGC CTGAGCTCG CCCGTCACA AAGAGCTTCAACAGGGGA GAGTGT (SEQ ID NO: 225) iPS:392514 SEQ IDCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG CAGGTGCAGCTG NO: 225TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA GTGGAATCTGGGAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC GGAGGCGTGGTCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGA CAGCCTGGGAGGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT TCCCTGAGACTCTAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA CCTGTGCAGCCTCCAATGACACGGGACACCTCAACCAGTACACTCTA TGGATTCACCTTCTATGGAACTGTCTAGCCTGAGATCCGAGGACACC AGTAGCTTTGGCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT ATGCACTGGGTCGACGGGTTATCCTGATTACTGGGGGCAGGGGACA CGCGAGGCTCCACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC GGCAAGGGGCTGATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA GAGTGGGTGGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT GTTATATCATTTGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG ATGGAAGTATTATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA AGTATTCTGTAGACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC CTCCGTGAAGGGTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CCGATTCACCATCGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCCAGAGACAATTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TCAAAGAACACGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA CTGTTTCTGCAAATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG TGAACAGCCTGCGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GAGCCGAGGACAGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CGGCTGTGTATTACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC CTGTGCGAGAGATGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG TCGGCTCAATTACGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG TATGATAGTAGTAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT GGTTATTATCACTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC ACAAATACTACGAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTATGGCCGTCTGTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC GGGCCAAGGAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC AACAGTTACCGTCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC CTCTAGTGGTCAGAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA CCCAAGGCCAACTCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT CCCACTGTCACTCGGGCAGCCGGAGAACAACTACAAGACCACGCCTC TGTTCCCGCCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT CTCTGAGGAGCTAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CCAAGCCAACAACAGGGGAACGTCTTCTCATGCTCCGTGATGCATG GGCCACACTAGTAGGCTCTGCACAACCACTACACGCAGAAGAGCCT GTGTCTGATCAGTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT GACTTCTACCCGGGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT GAGCTGTGACAGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT TGGCCTGGAAGGCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT CAGATGGCAGCCAATTATGTATCCTGGTACCAGAAGCTCCCAGGAA CCGTCAAGGCGGCAGCCCCCAAACTCCTCATTTATGACAATAATAA GAGTGGAGACCAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT CCAAACCCTCCACCAAGTCTGGCACGTCAACCACCCTGGGCATCAC AACAGAGCAACACGGACTCCAGACTGGGGACGAGGCCGATTATTAC ACAAGTACGCGGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG CCGAAAGCTACCTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGC TGAGCCTGACGCTAGTACAAAGGGCCCCTCCGTCTTTCCACTCGCAC CCGAGCAGTGGACCAGTTCAAAGTCCACTTCTGGAGGCACTGCGGC AGTCCCACAGAACTTGGGCTGTTTGGTGAAAGACTACTTCCCAGAG GCTACAGCTGCCCCAGTGACAGTCTCTTGGAATAGCGGAGCACTGA AGGTCACGCATGCCAGCGGTGTGCATACCTTTCCAGCTGTGCTGCAG AAGGGAGCACCGAGCAGCGGCCTCTACTCACTGAAGAGTGTCGTCA TGGAGAAGACAGCCGTTCCCTCTTCCAGCCTCGGCACTCAAACTTAC TGGCCCCTACAGATCTGCAACGTGAATCATAAGCCATCTAACACCA AATGTTCA AGGTAGACAAGAAAGTC (SEQ ID(SEQ ID NO: 598) NO: 622) iPS:392475 SEQ IDCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG CAGGTGCAGCTG NO: 225TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA GTGGAATCTGGGAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC GGAGGCGTGGTCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGA CAGCCTGGGAGGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT TCCCTGAGACTCTAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA CCTGTGCAGCCTCCAATGACACGGGACACCTCAACCAGTACACTCTA TGGATTCACCTTCTATGGAACTGTCTAGCCTGAGATCCGAGGACACC AGTAGCTTTGGCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT ATGCACTGGGTCGACGGGTTATCCTGATTACTGGGGGCAGGGGACA CGCCAGGCTCCACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC GGCAAGGGGCTGATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA GAGTGGGTGGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT GTTATATCATTTGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG ATGGAAGTATTATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA AGTATTCTGTAGACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC CTCCGTGAAGGGTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CCGATTCACCATCGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCCAGAGACAATTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TCAAAGAACACGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA CTGTTTCTGCAAATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG TGAACAGCCTGCGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GAGCCGAGGACAGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CGGCTGTGTATTACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC CTGTGCGAGAGATGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG TCGGCTCAATTACGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG TATGAAAGTAGTAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT GGTTATTATCACTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC ACAAATACTACGAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTATGGCCGTCTGTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC GGGCCAAGGAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC AACAGTTACCGTCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC CTCTAGTGGTCAGAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA CCCAAGGCCAACTCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT CCCACTGTCACTCGGGCAGCCGGAGAACAACTACAAGACCACGCCTC TGTTCCCGCCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT CTCTGAGGAGCTAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CCAAGCCAACAACAGGGGAACGTCTTCTCATGCTCCGTGATGCATG GGCCACACTAGTAGGCTCTGCACAACCACTACACGCAGAAGAGCCT GTGTCTGATCAGTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT GACTTCTACCCGGGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT GAGCTGTGACAGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT TGGCCTGGAAGGCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT CAGATGGCAGCCAATTATGTATCCTGGTACCAGCAGCTCCCAGGAA CCGTCAAGGCGGCAGCCCCCAAACTCCTCATTTATGACAATAATAA GAGTGGAGACCAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT CCAAACCCTCCACCAAGTCTGGCACGTCAACCACCCTGGGCATCAC AACAGAGCAACACGGACTCCAGACTGGGGACGAGGCCGATTATTAC ACAAGTACGCGGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG CCGAAAGCTACCTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGC TGAGCCTGACGCTAGTACAAAGGGCCCCTCCGTCTTTCCACTCGCAC CCGAGCAGTGGACCAGTTCAAAGTCCACTTCTGGAGGCACTGCGGC AGTCCCACAGAACTTGGGCTGTTTGGTGAAAGACTACTTCCCAGAG GCTACAGCTGCCCCAGTGACAGTCTCTTGGAATAGCGGAGCACTGA AGGTCACGCATGCCAGCGGTGTGCATACCTTTCCAGCTGTGCTGCAG AAGGGAGCACCGAGCAGCGGCCTCTACTCACTGAAGAGTGTCGTCA TGGAGAAGACAGCCGTTCCCTCTTCCAGCCTCGGCACTCAAACTTAC TGGCCCCTACAGATCTGCAACGTGAATCATAAGCCATCTAACACCA AATGTTCA AGGTAGACAAGAAAGTC (SEQ ID(SEQ ID NO: 599) NO: 623) iPS:392519 SEQ IDCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG CAGGTGCAGCTG NO: 225TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA GTGGAATCTGGGAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC GGAGGCGTGGTCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGA CAGCCTGGGAGGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT TCCCTGAGACTCTAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA CCTGTGCAGCCTCCAATGACACGGGACACCTCAACCAGTACACTCTA TGGATTCACCTTCTATGGAACTGTCTAGCCTGAGATCCGAGGACACC AGTAGCTTTGGCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT ATGCACTGGGTCGACGGGTTATCCTGATTACTGGGGGCAGGGGACA CGCGAGGCTCCACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC GGCAAGGGGCTGATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA GAGTGGGTGGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT GTTATATCATTTGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG ATGGAAGTATTATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA AGTATTCTGTAGACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC CTCCGTGAAGGGTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CCGATTCACCATCGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCCAGAGACAATTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TCAAAGAACACGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA CTGTTTCTGCAAATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG TGAACAGCCTGCGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GAGCCGAGGACAGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CGGCTGTGTATTACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC CTGTGCGAGAGATGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG TCGGCTCAATTACGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG TATGAAAGTAGTAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT GGTTATTATCACTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC ACAAATACTACGAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTATGGCCGTCTGTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC GGGCCAAGGAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC AACAGTTACCGTCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC CTCTAGTGGTCAGAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA CCCAAGGCCAACTCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT CCCACTGTCACTCGGGCAGCCGGAGAACAACTACAAGACCACGCCTC TGTTCCCGCCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT CTCTGAGGAGCTAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CCAAGCCAACAACAGGGGAACGTCTTCTCATGCTCCGTGATGCATG GGCCACACTAGTAGGCTCTGCACAACCACTACACGCAGAAGAGCCT GTGTCTGATCAGTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT GACTTCTACCCGGGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT GAGCTGTGACAGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT TGGCCTGGAAGGCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT CAGATGGCAGCCAATTATGTATCCTGGTACCAGAAGCTCCCAGGAA CCGTCAAGGCGGCAGCCCCCAAACTCCTCATTTATGACAATAATAA GAGTGGAGACCAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT CCAAACCCTCCACCAAGTCTGGCACGTCAACCACCCTGGGCATCAC AACAGAGCAACACGGACTCCAGACTGGGGACGAGGCCGATTATTAC ACAAGTACGCGGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG CCGAAAGCTACCTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGC TGAGCCTGACGCTAGTACAAAGGGCCCCTCCGTCTTTCCACTCGCAC CCGAGCAGTGGACCAGTTCAAAGTCCACTTCTGGAGGCACTGCGGC AGTCCCACAGAACTTGGGCTGTTTGGTGAAAGACTACTTCCCAGAG GCTACAGCTGCCCCAGTGACAGTCTCTTGGAATAGCGGAGCACTGA AGGTCACGCATGCCAGCGGTGTGCATACCTTTCCAGCTGTGCTGCAG AAGGGAGCACCGAGCAGCGGCCTCTACTCACTGAAGAGTGTCGTCA TGGAGAAGACAGCCGTTCCCTCTTCCAGCCTCGGCACTCAAACTTAC TGGCCCCTACAGATCTGCAACGTGAATCATAAGCCATCTAACACCA AATGTTCA AGGTAGACAAGAAAGTC (SEQ ID(SEQ ID NO: 600) NO: 624) iPS:392515 SEQ IDCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG CAGGTGCAGCTG NO: 225TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA GTGGAATCTGGGAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC GGAGGCGTGGTCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGA CAGCCTGGGAGGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT TCCCTGAGACTCTAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA CCTGTGCAGCCTCCAATGACACGGGACACCTCAACCAGTACACTCTA TGGATTCACCTTCTATGGAACTGTCTAGCCTGAGATCCGAGGACACC AGTAGCTTTGGCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT ATGCACTGGGTCGACGGGTTATCCTGATTACTGGGGGCAGGGGACA CGCCAGGCTCCACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC GGCAAGGGGCTGATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA GAGTGGGTGGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT GTTATATCATTTGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG ATGGAAGTATTATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA AGTATTCTGTAGACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC CTCCGTGAAGGGTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CCGATTCACCATCGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCCAGAGACAATTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TCAAAGAACACGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA CTGTTTCTGCAAATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG TGAACAGCCTGCGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GAGCCGAGGACAGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CGGCTGTGTATTACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC CTGTGCGAGAGATGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG TCGGCTCAATTACGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG TATGATAGTAGTAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT GGTTATTATCACTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC ACAAATACTACGAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTATGGCCGTCTGTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC GGGCCAAGGAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC AACAGTTACCGTCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC CTCTAGTGCCTCCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA ACCAAGGGCCCATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT TCGGTCTTCCCCCGGGCAGCCGGAGAACAACTACAAGACCACGCCTC TGGCACCCTCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT CAAGAGCACCTCAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG TGGGGGCACAGCCAGGGGAACGTCTTCTCATGCTCCGTGATGCATG GGCCCTGGGCTGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CCTGGTCAAGGAAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT CTACTTCCCCGAAGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT CCGGTGACGGTGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT TCGTGGAACTCACTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT GGCGCCCTGACCAATTATGTATCCTGGTACCAGCAGCTCCCAGGAA AGCGGCGTGCACCAGCCCCCAAACTCCTCATTTATGACAATAATAA ACCTTCCCGGCTGGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT TCCTACAGTCCTCCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC AGGACTCTACTCCCGGACTCCAGACTGGGGACGAGGCCGATTATTAC CTCGAAAGCGTGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG GTGACCGTGCCCTTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGG CCAGCAGCTTGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCC GCACCCAGACCTCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGC ACATCTGCAACGCACACTAGTGTGTCTGATCAGTGACTTCTACCCGG TGAATCACAAGCGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAG CCAGCAACACCACCCCGTCAAGGCGGGAGTGGAGACCACCAAACCC AGGTGGACAAGATCCAAACAGAGCAACAACAAGTACGCGGCCAAG AAGTTAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGT (SEQ IDCCCACAGAAGCTACAGCTGCCAGGTCACGCATGA NO: 625)AGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC AGAATGTTCA (SEQ ID NO: 601) iPS:392516SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG CAGGTGCAGCTG NO: 225TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA GTGGAATCTGGGAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC GGAGGCGTGGTCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGA CAGCCTGGGAGGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT TCCCTGAGACTCTAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA CCTGTGCAGCCTCCAATGACACGGGACACCTCAACCAGTACACTCTA TGGATTCACCTTCTATGGAACTGTCTAGCCTGAGATCCGAGGACACC AGTAGCTTTGGCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT ATGCACTGGGTCGACGGGTTATCCTGATTACTGGGGGCAGGGGACA CGCGAGGCTCCACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC GGCAAGGGGCTGATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA GAGTGGGTGGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT GTTATATCATTTGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG ATGGAAGTATTATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA AGTATTCTGTAGACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC CTCCGTGAAGGGTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CCGATTCACCATCGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCCAGAGACAATTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TCAAAGAACACGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA CTGTTTCTGCAAATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG TGAACAGCCTGCGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GAGCCGAGGACAGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CGGCTGTGTATTACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC CTGTGCGAGAGATGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG TCGGCTCAATTACGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG TATGATAGTAGTAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT GGTTATTATCACTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC ACAAATACTACGAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTATGGCCGTCTGTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC GGGCCAAGGAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC AACAGTTACCGTCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC CTCTAGTGCCTCCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA ACCAAGGGCCCATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT TCGGTCTTCCCCCGGGCAGCCGGAGAACAACTACAAGACCACGCCTC TGGCACCCTCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT CAAGAGCACCTCAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG TGGGGGCACAGCCAGGGGAACGTCTTCTCATGCTCCGTGATGCATG GGCCCTGGGCTGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CCTGGTCAAGGAAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT CTACTTCCCCGAAGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT CCGGTGACGGTGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT TCGTGGAACTCACTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT GGCGCCCTGACCAATTATGTATCCTGGTACCAGAAGCTCCCAGGAA AGCGGCGTGCACCAGCCCCCAAACTCCTCATTTATGACAATAATAA ACCTTCCCGGCTGGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT TCCTACAGTCCTCCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC AGGACTCTACTCCCGGACTCCAGACTGGGGACGAGGCCGATTATTAC CTCGAAAGCGTGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG GTGACCGTGCCCTTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGG CCAGCAGCTTGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCC GCACCCAGACCTCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGC ACATCTGCAACGCACACTAGTGTGTCTGATCAGTGACTTCTACCCGG TGAATCACAAGCGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAG CCAGCAACACCACCCCGTCAAGGCGGGAGTGGAGACCACCAAACCC AGGTGGACAAGATCCAAACAGAGCAACAACAAGTACGCGGCCAAG AAGTTAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGT (SEQ IDCCCACAGAAGCTACAGCTGCCAGGTCACGCATGA NO: 626)AGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC AGAATGTTCA (SEQ ID NO: 602) iPS:392521SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG CAGGTGCAGCTG NO: 225TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA GTGGAATCTGGGAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC GGAGGCGTGGTCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGA CAGCCTGGGAGGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT TCCCTGAGACTCTAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA CCTGTGCAGCCTCCAATGACACGGGACACCTCAACCAGTACACTCTA TGGATTCACCTTCTATGGAACTGTCTAGCCTGAGATCCGAGGACACC AGTAGCTTTGGCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT ATGCACTGGGTCGACGGGTTATCCTGATTACTGGGGGCAGGGGACA CGCGAGGCTCCACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC GGCAAGGGGCTGATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA GAGTGGGTGGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT GTTATATCATTTGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG ATGGAAGTATTATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA AGTATTCTGTAGACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC CTCCGTGAAGGGTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CCGATTCACCATCGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCCAGAGACAATTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TCAAAGAACACGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA CTGTTTCTGCAAATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG TGAACAGCCTGCGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GAGCCGAGGACAGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CGGCTGTGTATTACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC CTGTGCGAGAGATGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG TCGGCTCAATTACGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG TATGAAAGTAGTAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT GGTTATTATCACTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC ACAAATACTACGAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTATGGCCGTCTGTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC GGGCCAAGGAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC AACAGTTACCGTCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC CTCTAGTGCCTCCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA ACCAAGGGCCCATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT TCGGTCTTCCCCCGGGCAGCCGGAGAACAACTACAAGACCACGCCTC TGGCACCCTCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT CAAGAGCACCTCAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG TGGGGGCACAGCCAGGGGAACGTCTTCTCATGCTCCGTGATGCATG GGCCCTGGGCTGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CCTGGTCAAGGAAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT CTACTTCCCCGAAGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT CCGGTGACGGTGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT TCGTGGAACTCACTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT GGCGCCCTGACCAATTATGTATCCTGGTACCAGAAGCTCCCAGGAA AGCGGCGTGCACCAGCCCCCAAACTCCTCATTTATGACAATAATAA ACCTTCCCGGCTGGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT TCCTACAGTCCTCCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC AGGACTCTACTCCCGGACTCCAGACTGGGGACGAGGCCGATTATTAC CTCGAAAGCGTGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG GTGACCGTGCCCTTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGG CCAGCAGCTTGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCC GCACCCAGACCTCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGC ACATCTGCAACGCACACTAGTGTGTCTGATCAGTGACTTCTACCCGG TGAATCACAAGCGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAG CCAGCAACACCACCCCGTCAAGGCGGGAGTGGAGACCACCAAACCC AGGTGGACAAGATCCAAACAGAGCAACAACAAGTACGCGGCCAAG AAGTTAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGT (SEQ IDCCCACAGAAGCTACAGCTGCCAGGTCACGCATGA NO: 627)AGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC AGAATGTTCA (SEQ ID NO: 603) iPS:392520SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG CAGGTGCAGCTG NO: 225TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA GTGGAATCTGGGAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC GGAGGCGTGGTCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGA CAGCCTGGGAGGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT TCCCTGAGACTCTAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA CCTGTGCAGCCTCCAATGACACGGGACACCTCAACCAGTACACTCTA TGGATTCACCTTCTATGGAACTGTCTAGCCTGAGATCCGAGGACACC AGTAGCTTTGGCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT ATGCACTGGGTCGACGGGTTATCCTGATTACTGGGGGCAGGGGACA CGCCAGGCTCCACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC GGCAAGGGGCTGATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA GAGTGGGTGGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT GTTATATCATTTGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG ATGGAAGTATTATGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA AGTATTCTGTAGACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC CTCCGTGAAGGGTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CCGATTCACCATCGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCCAGAGACAATTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TCAAAGAACACGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA CTGTTTCTGCAAATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG TGAACAGCCTGCGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GAGCCGAGGACAGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CGGCTGTGTATTACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC CTGTGCGAGAGATGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG TCGGCTCAATTACGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG TATGAAAGTAGTAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT GGTTATTATCACTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC ACAAATACTACGAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTATGGCCGTCTGTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC GGGCCAAGGAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC AACAGTTACCGTCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC CTCTAGTGCCTCCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA ACCAAGGGCCCATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT TCGGTCTTCCCCCGGGCAGCCGGAGAACAACTACAAGACCACGCCTC TGGCACCCTCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT CAAGAGCACCTCAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG TGGGGGCACAGCCAGGGGAACGTCTTCTCATGCTCCGTGATGCATG GGCCCTGGGCTGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CCTGGTCAAGGAAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT CTACTTCCCCGAAGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT CCGGTGACGGTGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT TCGTGGAACTCACTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT GGCGCCCTGACCAATTATGTATCCTGGTACCAGCAGCTCCCAGGAA AGCGGCGTGCACCAGCCCCCAAACTCCTCATTTATGACAATAATAA ACCTTCCCGGCTGGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT TCCTACAGTCCTCCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC AGGACTCTACTCCCGGACTCCAGACTGGGGACGAGGCCGATTATTAC CTCGAAAGCGTGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG GTGACCGTGCCCTTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGG CCAGCAGCTTGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCC GCACCCAGACCTCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGC ACATCTGCAACGCACACTAGTGTGTCTGATCAGTGACTTCTACCCGG TGAATCACAAGCGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAG CCAGCAACACCACCCCGTCAAGGCGGGAGTGGAGACCACCAAACCC AGGTGGACAAGATCCAAACAGAGCAACAACAAGTACGCGGCCAAG AAGTTAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGT (SEQ IDCCCACAGAAGCTACAGCTGCCAGGTCACGCATGA NO: 628)AGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC AGAATGTTCA (SEQ ID NO: 604) iPS:392517GATATCCAG CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG SEQ ID CTCACTCAATAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA NO: 625 TCGCCATCAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC TTTCTCTCCGATTGGGTGCGGAAAGCTCCCGGTCAGGGGTTGGA CTTCGGTAGGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT GCGACCGGGAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCA TCACGATCACAATGACACGGGACACCTCAACCAGTACACTCTA CATGCAGGGTATGGAACTGTCTAGCCTGAGATCCGAGGACACC CGTCGCAAAGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT GCATTGGGAGACGGGTTATCCTGATTACTGGGGGCAGGGGACA GGTCGTTGCCTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC ATTGGTATCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA AGGAGAAACCCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT CCGGAAAGGCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG CCCCGAAACTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA TTCTGATCACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC AATACGCATTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA CACAAAGTTGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TGAGCGGTGTCACAAGCCCAGCAACACCAAGGTGGACAAGAA TGCCGTCGCAGTTGAGCCCAAATCTTGTGACAAAACTCACACA GCTTCTCCGTGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG GTTCCGGAAGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GCGGAACGGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA AGTTCACGCCATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TTACAATCTTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG CCTCACTGCGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGG AGCCCGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT ATTTCGCGACCTCACCGTCCTGCACCAGGACTGGCTGAATGGC CCTATTACTAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC GTCACCAGTTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGC CATCCAGACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC TCCCGTTTACCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC TTTTGGCCCTAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA GGGACCAAGTCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT GTGGACATTGGGCAGCCGGAGAACAACTACAAGACCACGCCTC AAGCGTACGCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAT GTGGCTGCAAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CCATCTGTCTCAGGGGAACGTCTTCTCATGCTCCGTGATGCATG TCATCTTCCCAGGCTCTGCACAACCACTACACGCAGAAGAGCCT GCCATCTGAAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGT TGAGCAGTTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT GAAATCTGGCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCAT AACTGCCTCCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT TGTTGTGTGAATTATGTATCCTGGTACCAGCAGCTCCCAGGAA CCTGCTGAACAGCCCCCAAACTCCTCATTTATGACAATAATAA TAACTTCTATGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCT CCCAGAGAGCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC GCCAAAGTACGGACTCCAGACTGGGGACGAGGCCGATTATTAC CAGTGGAAGTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG GTGGATAACTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGG GCCCTCCAATCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCC TCGGGTAACCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGC TCCCAGGAGCACACTAGTGTGTCTGATCAGTGACTTCTACCCGG AGTGTCACAGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAG GAGCAGGACCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCC AGCAAGGACTCCAAACAGAGCAACAACAAGTACGCGGCCAAG AGCACCTACAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGT AGCCTCGAACCCACAGAAGCTACAGCTGCCAGGTCACGCATGA AGCACCCTGAGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC ACGCTGAGC AGAATGTTCA (SEQ ID NO: 605)AAAGCAGAC TACGAGAAA CACAAAGTC TACGCCTGC GAAGTCACC CATCAGGGC CTGAGCTCGCCCGTCACA AAGAGCTTC AACAGGGGA GAGTGT (SEQ ID NO: 595) iPS:392518 SEQ IDCAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG SEQ ID NO: 595TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA NO: 626AGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC ATTGGGTGCGGAAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT AAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTA TATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT GACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT CAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA CCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA GCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAA AGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG GACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC TCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC CTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTC CCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT AAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT CAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT AATTATGTATCCTGGTACCAGAAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAA GCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC CGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG TTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCC CGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGG GAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCC TCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGT CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC AGAATGTTCA (SEQ ID NO: 606) iPS:392522SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG SEQ ID NO: 595TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA NO: 628AGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC ATTGGGTGCGGAAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT AAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTA TATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT GACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT CAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA CCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA GCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAA AGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG GACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC TCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC CTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTC CCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT AAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT CAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT AATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAA GCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC CGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG TTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCC CGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGG GAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCC TCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGT CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC AGAATGTTCA (SEQ ID NO: 607) iPS:392523SEQ ID CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAG SEQ ID NO: 595TAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAA NO: 627AGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGC ATTGGGTGCGGAAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAAT AAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTA TATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATT GACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTAGTGCCTCCACCAAGGGCCC ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT CAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA CCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAAAAGCGTGGTGACCGTGCCCTCCAGCA GCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAA AGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG GACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCAGTACGGCAGCACGTACCGTTGTGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC TCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC CTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTC CCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT AAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCT CAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAAT AATTATGTATCCTGGTACCAGAAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAA GCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAACCACCCTGGGCATCAC CGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCCGCCTGAGTGCTGTGG TTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCC CGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGG GAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCC TCCAAACAGAGCAACAACAAGTACGCGGCCAAGAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGT CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC AGAATGTTCA (SEQ ID NO: 608)Anti-CGRP Receptor IgG x Anti-PAC1 Receptor Fab iPS:392524 CAGTCTGTGCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG CAAGTTCAGTTG TTGACGCAGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC GTGGAGTCTGGA CCGCCCTCAAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GCCGAAGTAGTA GTGTCTGCGACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA AAGCCAGGAGCT GCCCCAGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT TCAGTGAAAGTC CAGAAGGTCAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA TCTTGTAAAGCA ACCATCTCCCCATCTCCAGAGACAATTCAAAGAACACGCTGTT AGTGGATTCACG TGCTCTGGATCTGCAAATGAACAGCCTGCGAGCCGAGGACACG TTTAGCCGCTTTG AGCAGCTCCGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT CCATGCATTGGGT AACATTGGGACTATGATAGTAGTGGTTATTATCACTACAAATAC GCGGCAAGCTCC AATAATTATTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG CGGTCAGGGGTT GTATCCTGGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG GGAGTGGATGGG TACCAGCAGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC AGTTATTAGCTAT CTCCCAGGATGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACGGGGGCAAT ACAGCCCCCGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA AAGTACTACGCC AAACTCCTCACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT GAGTCTGTTAAG ATTTATGACCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC GGTCGGGTCACA AATAATAAGTCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTT ATGACACGGGAC CGACCCTCAGGGCACCCAGACCTACATCTGCAACGTGAATCAC ACCTCAACCAGT GGGATTCCTAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT ACACTCTATATGG GACCGATTCGAGCCCAAATCTTGTGACAAAACTCACACATGCC AACTGTCTAGCCT TCTGGCTCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC GAGATCCGAGGA AAGTCTGGCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA CACCGCTGTGTAT ACGTCAACCCCCTCATGATCTCCCGGACCCCTGAGGTCACATGC TATTGCGCTAGG ACCCTGGGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG GGGTACGATGTA ATCACCGGATCAAGTTCAACTGGTACGTGGACGGCGTGGAGGT TTGACGGGTTATC CTCCAGACTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCA CTGATTACTGGG GGGGACGAGGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTC GGCAGGGGACAC GCCGATTATACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG TCGTAACCGTCTC TACTGCGGAAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC TAGTACGGTGGC ACATGGGATAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA TGCACCATCTGTC AGCCGCCTGGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC TTCATCTTCCCGC AGTGCTGTGCCCCATCCCGGGAGGAGATGACCAAGAACCAGGT CATCTGATGAGC GTTTTCGGCCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA AGTTGAAATCTG GGAGGGACCGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC GAACTGCCTCTGT AAGCTGACCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT TGTGTGCCTGCTG GTCCTAGGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCA AATAACTTCTATC CAGCCCAAGAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG CCAGAGAGGCCA GCCAACCCCGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT AAGTACAGTGGA ACTGTCACTCTGCACAACCACTACACGCAGAAGAGCCTAAGCT AGGTGGATAACG CTGTTCCCGTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGG CCCTCCAATCGG CCCTCCTCTGATCCGATATCCAGCTCACTCAATCGCCATCATTTC GTAACTCCCAGG AGGAGCTCCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCAC AGAGTGTCACAG AAGCCAACAATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTG AGCAGGACAGCA AGGCCACACCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGA AGGACAGCACCT TAGTGTGTCAACTTCTGATCAAATACGCATCACAAAGTTTGAG ACAGCCTCAAGA TGATCAGTGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGC GCACCCTGACGC ACTTCTACCGGAACGGAGTTCACGCTTACAATCTCCTCACTGC TGAGCAAAGCAG CGGGAGCTGAGCCCGAGGATTTCGCGACCTATTACTGTCACCA ACTACGAGAAAC TGACAGTGGGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGA ACAAAGTCTACG CCTGGAAGGCCAAGGTGGACATTAAGCGTGCTAGTACAAAGGG CCTGCGAAGTCA CAGATGGCACCCCTCCGTCTTTCCACTCGCACCCAGTTCAAAGT CCCATCAGGGCC GCCCCGTCACCACTTCTGGAGGCACTGCGGCCTTGGGCTGTTTG TGAGCTCGCCCGT AGGCGGGAGGTGAAAGACTACTTCCCAGAGCCAGTGACAGTCT CACAAAGAGCTT TGGAGACCACTTGGAATAGCGGAGCACTGACCAGCGGTGTGCA CAACAGGGGAGA CCAAACCCTTACCTTTCCAGCTGTGCTGCAGAGCAGCGGCCTCT GTGT CCAAACAGAACTCACTGGAGAGTGTCGTCACCGTTCCCTCTTCC (SEQ ID GCAACAACAAGCCTCGGCACTCAAACTTACATCTGCAACGTGA NO: 629) AGTACGCGGATCATAAGCCATCTAACACCAAGGTAGACAAGAA CCAAGAGCT AGTC (SEQ ID NO: 609)ACCTGAGCC TGACGCCCG AGCAGTGGA AGTCCCACA GAAGCTACA GCTGCCAGG TCACGCATGAAGGGAGCA CCGTGGAGA AGACAGTGG CCCCTACAG AATGTTCA (SEQ ID NO: 287)iPS:392525 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG CAAGTTCAGTTGNO: 287 TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC GTGGAGTCTGGAAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GCCGAAGTAGTAACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA AAGCCAGGAGCTGTGGGTGGCAGTTATATCATTTGATGGAAGTATT TCAGTGAAAGTCAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA TCTTGTAAAGCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT AGTGGATTCACGTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG TTTAGCCGCTTTGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT CCATGCATTGGGTACTATGATAGTAGTGGTTATTATCACTACAAATAC GCGGAAAGCTCCTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG CGGTCAGGGGTTTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG GGAGTGGATGGGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC AGTTATTAGCTATTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACGGGGGCAATGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA AAGTACTACGCCACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT GAGTCTGTTAAGCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC GGTCGGGTCACATCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTT ATGACACGGGACGGGCACCCAGACCTACATCTGCAACGTGAATCAC ACCTCAACCAGTAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT ACACTCTATATGGGAGCCCAAATCTTGTGACAAAACTCACACATGCC AACTGTCTAGCCTCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC GAGATCCGAGGAGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA CACCGCTGTGTATCCCTCATGATCTCCCGGACCCCTGAGGTCACATGC TATTGCGCTAGGGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG GGGTACGATGTATCAAGTTCAACTGGTACGTGGACGGCGTGGAGGT TTGACGGGTTATCGCATAATGCCAAGACAAAGCCGTGTGAGGAGCA CTGATTACTGGGGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTC GGCAGGGGACACACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG TCGTAACCGTCTCAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC TAGTACGGTGGCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA TGCACCATCTGTCGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC TTCATCTTCCCGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGT CATCTGATGAGCCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA AGTTGAAATCTGGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC GAACTGCCTCTGTAGCCGGAGAACAACTACAAGACCACGCCTCCCGT TGTGTGCCTGCTGGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCA AATAACTTCTATCAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG CCAGAGAGGCCAGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT AAGTACAGTGGACTGCACAACCACTACACGCAGAAGAGCCTAAGCT AGGTGGATAACGTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGG CCCTCCAATCGGATCCGATATCCAGCTCACTCAATCGCCATCATTTC GTAACTCCCAGGTCTCCGCTTCGGTAGGCGACCGGGTCACGATCAC AGAGTGTCACAGATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTG AGCAGGACAGCACATTGGTATCAGGAGAAACCCGGAAAGGCCCCGA AGGACAGCACCTAACTTCTGATCAAATACGCATCACAAAGTTTGAG ACAGCCTCAAGACGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGC GCACCCTGACGCGGAACGGAGTTCACGCTTACAATCTCCTCACTGC TGAGCAAAGCAGAGCCCGAGGATTTCGCGACCTATTACTGTCACCA ACTACGAGAAACGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGA ACAAAGTCTACGCCAAGGTGGACATTAAGCGTGCTAGTACAAAGGG CCTGCGAAGTCACCCCTCCGTCTTTCCACTCGCACCCAGTTCAAAGT CCCATCAGGGCCCCACTTCTGGAGGCACTGCGGCCTTGGGCTGTTTG TGAGCTCGCCCGTGTGAAAGACTACTTCCCAGAGCCAGTGACAGTCT CACAAAGAGCTTCTTGGAATAGCGGAGCACTGACCAGCGGTGTGCA CAACAGGGGAGATACCTTTCCAGCTGTGCTGCAGAGCAGCGGCCTCT GTGTACTCACTGGAGAGTGTCGTCACCGTTCCCTCTTCC (SEQ IDAGCCTCGGCACTCAAACTTACATCTGCAACGTGA NO: 630)ATCATAAGCCATCTAACACCAAGGTAGACAAGAA AGTC (SEQ ID NO: 610) iPS:392526SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG SEQ ID NO: 287TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC NO: 629AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC ACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT TCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT ACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACA GTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCA CAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGC CCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC ACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGC AGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGC GGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATC ACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCC GAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAA GCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCAC CAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTGCTAGTACAAAG GGCCCCTCCGTCTTTCCACTCGCACCCAGTTCAAAGTCCACTTCTGGAGGCACTGCGGCCTTGGGCTGTT TGGTGAAAGACTACTTCCCAGAGCCAGTGACAGTCTCTTGGAATAGCGGAGCACTGACCAGCGGTGTG CATACCTTTCCAGCTGTGCTGCAGAGCAGCGGCCTCTACTCACTGGAGAGTGTCGTCACCGTTCCCTCT TCCAGCCTCGGCACTCAAACTTACATCTGCAACGTGAATCATAAGCCATCTAACACCAAGGTAGACAAG AAAGTC (SEQ ID NO: 611) iPS:392527SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG SEQ ID NO: 287TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC NO: 630AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC ACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT TCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT ACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACA GTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCA CAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGC CCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC ACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGC AGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGC GGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATC ACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGGAGAAACCCGGAAAGGCCCC GAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAA GCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCAC CAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTGCTAGTACAAAG GGCCCCTCCGTCTTTCCACTCGCACCCAGTTCAAAGTCCACTTCTGGAGGCACTGCGGCCTTGGGCTGTT TGGTGAAAGACTACTTCCCAGAGCCAGTGACAGTCTCTTGGAATAGCGGAGCACTGACCAGCGGTGTG CATACCTTTCCAGCTGTGCTGCAGAGCAGCGGCCTCTACTCACTGGAGAGTGTCGTCACCGTTCCCTCT TCCAGCCTCGGCACTCAAACTTACATCTGCAACGTGAATCATAAGCCATCTAACACCAAGGTAGACAAG AAAGTC (SEQ ID NO: 612) iPS:392528SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG CAAGTTCAGTTG NO: 287TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC GTGGAGTCTGGAAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GCCGAAGTAGTAACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA AAGCCAGGAGCTGTGGGTGGCAGTTATATCATTTGATGGAAGTATT TCAGTGAAAGTCAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA TCTTGTAAAGCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT AGTGGATTCACGTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG TTTAGCCGCTTTGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT CCATGCATTGGGTACTATGATAGTAGTGGTTATTATCACTACAAATAC GCGGCAAGCTCCTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG CGGTCAGGGGTTTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG GGAGTGGATGGGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC AGTTATTAGCTATTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACGGGGGCAATGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA AAGTACTACGCCACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT GAGTCTGTTAAGCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC GGTCGGGTCACATCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTT ATGACACGGGACGGGCACCCAGACCTACATCTGCAACGTGAATCAC ACCTCAACCAGTAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT ACACTCTATATGGGAGCCCAAATCTTGTGACAAAACTCACACATGCC AACTGTCTAGCCTCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC GAGATCCGAGGAGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA CACCGCTGTGTATCCCTCATGATCTCCCGGACCCCTGAGGTCACATGC TATTGCGCTAGGGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG GGGTACGATGTATCAAGTTCAACTGGTACGTGGACGGCGTGGAGGT TTGACGGGTTATCGCATAATGCCAAGACAAAGCCGTGTGAGGAGCA CTGATTACTGGGGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTC GGCAGGGGACACACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG TCGTAACCGTCTCAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC TAGTGCCTCCACCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA AAGGGCCCATCGGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC GTCTTCCCCCTGGCCCCATCCCGGGAGGAGATGACCAAGAACCAGGT CACCCTCCTCCAACAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GAGCACCTCTGGGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC GGGCACAGCGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT CCTGGGCTGCCTGGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCA GTCAAGGACTACAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG TTCCCCGAACCGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT GTGACGGTGTCGCTGCACAACCACTACACGCAGAAGAGCCTAAGCT TGGAACTCAGGCTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGG GCCCTGACCAGCATCCGATATCCAGCTCACTCAATCGCCATCATTTC GGCGTGCACACCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCAC TTCCCGGCTGTCCATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTG TACAGTCCTCAGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGA GACTCTACTCCCTAACTTCTGATCAAATACGCATCACAAAGTTTGAG CAAGAGCGTGGTCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGC GACCGTGCCCTCCGGAACGGAGTTCACGCTTACAATCTCCTCACTGC AGCAGCTTGGGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCA ACCCAGACCTACGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGA ATCTGCAACGTGCCAAGGTGGACATTAAGCGTACGGTGGCTGCACC AATCACAAGCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGT AGCAACACCAAGTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTG GTGGACAAGAAAAATAACTTCTATCCCAGAGAGGCCAAAGTACAGT GTTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTC (SEQ IDCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGA NO: 631)CAGCACCTACAGCCTCGAAAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 613) iPS:392529 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGCAAGTTCAGTTG NO: 287 TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC GTGGAGTCTGGAAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GCCGAAGTAGTAACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGA AAGCCAGGAGCTGTGGGTGGCAGTTATATCATTTGATGGAAGTATT TCAGTGAAAGTCAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA TCTTGTAAAGCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT AGTGGATTCACGTCTGCAAATGAACAGCCTGCGAGCCGAGGACACG TTTAGCCGCTTTGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT CCATGCATTGGGTACTATGATAGTAGTGGTTATTATCACTACAAATAC GCGGAAAGCTCCTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG CGGTCAGGGGTTTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG GGAGTGGATGGGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC AGTTATTAGCTATTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACGGGGGCAATGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA AAGTACTACGCCACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT GAGTCTGTTAAGCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC GGTCGGGTCACATCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTT ATGACACGGGACGGGCACCCAGACCTACATCTGCAACGTGAATCAC ACCTCAACCAGTAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT ACACTCTATATGGGAGCCCAAATCTTGTGACAAAACTCACACATGCC AACTGTCTAGCCTCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC GAGATCCGAGGAGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA CACCGCTGTGTATCCCTCATGATCTCCCGGACCCCTGAGGTCACATGC TATTGCGCTAGGGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG GGGTACGATGTATCAAGTTCAACTGGTACGTGGACGGCGTGGAGGT TTGACGGGTTATCGCATAATGCCAAGACAAAGCCGTGTGAGGAGCA CTGATTACTGGGGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTC GGCAGGGGACACACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG TCGTAACCGTCTCAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC TAGTGCCTCCACCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA AAGGGCCCATCGGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC GTCTTCCCCCTGGCCCCATCCCGGGAGGAGATGACCAAGAACCAGGT CACCCTCCTCCAACAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GAGCACCTCTGGGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC GGGCACAGCGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT CCTGGGCTGCCTGGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCA GTCAAGGACTACAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG TTCCCCGAACCGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT GTGACGGTGTCGCTGCACAACCACTACACGCAGAAGAGCCTAAGCT TGGAACTCAGGCTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGG GCCCTGACCAGCATCCGATATCCAGCTCACTCAATCGCCATCATTTC GGCGTGCACACCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCAC TTCCCGGCTGTCCATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTG TACAGTCCTCAGCATTGGTATCAGGAGAAACCCGGAAAGGCCCCGA GACTCTACTCCCTAACTTCTGATCAAATACGCATCACAAAGTTTGAG CAAGAGCGTGGTCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGC GACCGTGCCCTCCGGAACGGAGTTCACGCTTACAATCTCCTCACTGC AGCAGCTTGGGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCA ACCCAGACCTACGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGA ATCTGCAACGTGCCAAGGTGGACATTAAGCGTACGGTGGCTGCACC AATCACAAGCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGT AGCAACACCAAGTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTG GTGGACAAGAAAAATAACTTCTATCCCAGAGAGGCCAAAGTACAGT GTTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTC (SEQ IDCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGA NO: 632)CAGCACCTACAGCCTCGAAAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 614) iPS:392532 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGSEQ ID NO: 287 TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC NO: 631AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC ACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT TCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT ACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACA GTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCA CAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGC CCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC ACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGC AGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGC GGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATC ACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCC GAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAA GCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCAC CAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTACGGTGGCTGCA CCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAAAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 615) iPS:392533 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGSEQ ID NO: 287 TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC NO: 632AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC ACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT TCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT ACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACA GTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCA CAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGC CCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC ACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGC AGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGC GGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATC ACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGGAGAAACCCGGAAAGGCCCC GAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAA GCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCAC CAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTACGGTGGCTGCA CCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAAAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 616) iPS:392530 CAGTCTGTG CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGSEQ ID TTGACGCAG TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC NO: 631 CCGCCCTCAAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC GTGTCTGCGACTGGGTCCGCGAGGCTCCAGGCAAGGGGCTGGA GCCCCAGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT CAGAAGGTCAAGTATTCTGTAGACTCCGTGAAGGGCCGATTCA ACCATCTCCCCATCTCCAGAGACAATTCAAAGAACACGCTGTT TGCTCTGGATCTGCAAATGAACAGCCTGCGAGCCGAGGACACG AGCAGCTCCGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT AACATTGGGACTATGATAGTAGTGGTTATTATCACTACAAATAC AATAATTATTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG GTATCCTGGTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG TACCAGAAGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC CTCCCAGGATGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG ACAGCCCCCGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA AAACTCCTCACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT ATTTATGACCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC AATAATAAGTCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTT CGACCCTCAGGGCACCCAGACCTACATCTGCAACGTGAATCAC GGGATTCCTAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT GACCGATTCGAGCCCAAATCTTGTGACAAAACTCACACATGCC TCTGGCTCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC AAGTCTGGCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA ACGTCAACCCCCTCATGATCTCCCGGACCCCTGAGGTCACATGC ACCCTGGGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG ATCACCGGATCAAGTTCAACTGGTACGTGGACGGCGTGGAGGT CTCCAGACTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCA GGGGACGAGGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTC GCCGATTATACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG TACTGCGGAAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC ACATGGGATAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA AGCCGCCTGGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC AGTGCTGTGCCCCATCCCGGGAGGAGATGACCAAGAACCAGGT GTTTTCGGCCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GGAGGGACCGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC AAGCTGACCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GTCCTAGGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCA CAGCCCAAGAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG GCCAACCCCGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT ACTGTCACTCTGCACAACCACTACACGCAGAAGAGCCTAAGCT CTGTTCCCGTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGG CCCTCCTCTGATCCGATATCCAGCTCACTCAATCGCCATCATTTC AGGAGCTCCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCAC AAGCCAACAATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTG AGGCCACACCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGA TAGTGTGTCAACTTCTGATCAAATACGCATCACAAAGTTTGAG TGATCAGTGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGC ACTTCTACCGGAACGGAGTTCACGCTTACAATCTCCTCACTGC CGGGAGCTGAGCCCGAGGATTTCGCGACCTATTACTGTCACCA TGACAGTGGGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGA CCTGGAAGGCCAAGGTGGACATTAAGCGTACGGTGGCTGCACC CAGATGGCAATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGT GCCCCGTCATGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTG AGGCGGGAGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGT TGGAGACCAGGAAGGTGGATAACGCCCTCCAATCGGGTAACTC CCAAACCCTCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGA CCAAACAGACAGCACCTACAGCCTCGAAAGCACCCTGACGCTG GCAACAACAAGCAAAGCAGACTACGAGAAACACAAAGTCTAC AGTACGCGGGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCAAGAGCTCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT ACCTGAGCC (SEQ ID NO: 617) TGACGCCCGAGCAGTGGA AGTCCCACA GAAGCTACA GCTGCCAGG TCACGCATG AAGGGAGCA CCGTGGAGAAGACAGTGG CCCCTACAG AATGTTCA (SEQ ID NO: 596) iPS:392531 SEQ IDCAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGG SEQ ID NO: 596TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC NO: 632AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC ACTGGGTCCGCGAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT TCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT ACTATGATAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACAG TTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC TGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGA ACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCAC AAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCC CACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA CCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGCA GTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG AGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA GGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCA AGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGCGG ATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATCAC ATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGGAGAAACCCGGAAAGGCCCCGA AACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGC GGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCA GTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTACGGTGGCTGCACC ATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTG AATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTC CCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAAAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 618) iPS:392534 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGSEQ ID NO: 596 TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC NO: 631AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC ACTGGGTCCGCGAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT TCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT ACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACA GTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCA CAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGC CCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC ACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGC AGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGC GGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATC ACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCC GAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAA GCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCAC CAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTACGGTGGCTGCA CCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAAAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 619) iPS:392535 SEQ ID CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGSEQ ID NO: 596 TCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGC NO: 632AGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGC ACTGGGTCCGCGAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTTGATGGAAGTATT AAGTATTCTGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCAAAGAACACGCTGTT TCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGGCTCAATT ACTATGAAAGTAGTGGTTATTATCACTACAAATACTACGGTATGGCCGTCTGGGGCCAAGGGACAACA GTTACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCGAAAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCA CAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGC CCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC ACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGTGTGAGGAGC AGTACGGCAGCACGTACCGTTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGAGCCTAAGCTTGTCTCCGGGTGGTGGCGGATCGGGAGGTGGC GGATCCGATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGCTTCGGTAGGCGACCGGGTCACGATC ACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGGAGAAACCCGGAAAGGCCCC GAAACTTCTGATCAAATACGCATCACAAAGTTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAA GCGGAACGGAGTTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCAC CAGTCATCCAGACTCCCGTTTACTTTTGGCCCTGGGACCAAGGTGGACATTAAGCGTACGGTGGCTGCA CCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCGAAAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO: 620)

The nucleic acid sequences provided in Tables 6A, 6B, 7A, 7B, and 11-14are exemplary only. As will be appreciated by those in the art, due tothe degeneracy of the genetic code, an extremely large number of nucleicacids may be made, all of which encode the CDRs (and heavy and lightchains or other components of the antigen binding proteins describedherein) of the invention. Thus, having identified a particular aminoacid sequence, those skilled in the art could make any number ofdifferent nucleic acids, by simply modifying the sequence of one or morecodons in a way which does not change the amino acid sequence of theencoded protein.

The present invention also includes vectors comprising one or morenucleic acids encoding one or more components of the bispecific antigenbinding proteins of the invention (e.g. variable regions, light chains,heavy chains, modified heavy chains, and Fd fragments). The term“vector” refers to any molecule or entity (e.g., nucleic acid, plasmid,bacteriophage or virus) used to transfer protein coding information intoa host cell. Examples of vectors include, but are not limited to,plasmids, viral vectors, non-episomal mammalian vectors and expressionvectors, for example, recombinant expression vectors. The term“expression vector” or “expression construct” as used herein refers to arecombinant DNA molecule containing a desired coding sequence andappropriate nucleic acid control sequences necessary for the expressionof the operably linked coding sequence in a particular host cell. Anexpression vector can include, but is not limited to, sequences thataffect or control transcription, translation, and, if introns arepresent, affect RNA splicing of a coding region operably linked thereto.Nucleic acid sequences necessary for expression in prokaryotes include apromoter, optionally an operator sequence, a ribosome binding site andpossibly other sequences. Eukaryotic cells are known to utilizepromoters, enhancers, and termination and polyadenylation signals. Asecretory signal peptide sequence can also, optionally, be encoded bythe expression vector, operably linked to the coding sequence ofinterest, so that the expressed polypeptide can be secreted by therecombinant host cell, for more facile isolation of the polypeptide ofinterest from the cell, if desired. For instance, in some embodiments,signal peptide sequences may be appended/fused to the amino terminus ofany of the polypeptides sequences listed in Tables 6A, 6B, 7A, 7B, 9 and10. In certain embodiments, a signal peptide having the amino acidsequence of MDMRVPAQLLGLLLLWLRGARC (SEQ ID NO: 633) is fused to theamino terminus of any of the polypeptide sequences in Tables 6A, 6B, 7A,7B, 9 and 10. In other embodiments, a signal peptide having the aminoacid sequence of MAWALLLLTLLTQGTGSWA (SEQ ID NO: 634) is fused to theamino terminus of any of the polypeptide sequences in Tables 6A, 6B, 7A,7B, 9 and 10. In still other embodiments, a signal peptide having theamino acid sequence of MTCSPLLLTLLIHCTGSWA (SEQ ID NO: 635) is fused tothe amino terminus of any of the polypeptide sequences in Tables 6A, 6B,7A, 7B, 9 and 10. Other suitable signal peptide sequences that can befused to the amino terminus of the polypeptide sequences describedherein include: MEAPAQLLFLLLLWLPDTTG (SEQ ID NO: 636),MEWTWRVLFLVAAATGAHS (SEQ ID NO: 637), METPAQLLFLLLLWLPDTTG (SEQ ID NO:638), METPAQLLFLLLLWLPDTTG (SEQ ID NO: 639), MKHLWFFLLLVAAPRWVLS (SEQ IDNO: 640), and MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 641). Other signalpeptides are known to those of skill in the art and may be fused to anyof the polypeptide chains listed in Tables 6A, 6B, 7A, 7B, 9 and 10, forexample, to facilitate or optimize expression in particular host cells.

Typically, expression vectors used in the host cells to produce thebispecific antigen proteins of the invention will contain sequences forplasmid maintenance and for cloning and expression of exogenousnucleotide sequences encoding the components of the bispecific antigenbinding proteins. Such sequences, collectively referred to as “flankingsequences,” in certain embodiments will typically include one or more ofthe following nucleotide sequences: a promoter, one or more enhancersequences, an origin of replication, a transcriptional terminationsequence, a complete intron sequence containing a donor and acceptorsplice site, a sequence encoding a leader sequence for polypeptidesecretion, a ribosome binding site, a polyadenylation sequence, apolylinker region for inserting the nucleic acid encoding thepolypeptide to be expressed, and a selectable marker element. Each ofthese sequences is discussed below.

Optionally, the vector may contain a “tag”-encoding sequence, i.e., anoligonucleotide molecule located at the 5′ or 3′ end of the polypeptidecoding sequence; the oligonucleotide tag sequence encodes polyHis (suchas hexaHis), FLAG, HA (hemaglutinin influenza virus), myc, or another“tag” molecule for which commercially available antibodies exist. Thistag is typically fused to the polypeptide upon expression of thepolypeptide, and can serve as a means for affinity purification ordetection of the polypeptide from the host cell. Affinity purificationcan be accomplished, for example, by column chromatography usingantibodies against the tag as an affinity matrix. Optionally, the tagcan subsequently be removed from the purified polypeptide by variousmeans such as using certain peptidases for cleavage.

Flanking sequences may be homologous (i.e., from the same species and/orstrain as the host cell), heterologous (i.e., from a species other thanthe host cell species or strain), hybrid (i.e., a combination offlanking sequences from more than one source), synthetic or native. Assuch, the source of a flanking sequence may be any prokaryotic oreukaryotic organism, any vertebrate or invertebrate organism, or anyplant, provided that the flanking sequence is functional in, and can beactivated by, the host cell machinery.

Flanking sequences useful in the vectors of this invention may beobtained by any of several methods well known in the art. Typically,flanking sequences useful herein will have been previously identified bymapping and/or by restriction endonuclease digestion and can thus beisolated from the proper tissue source using the appropriate restrictionendonucleases. In some cases, the full nucleotide sequence of a flankingsequence may be known. Here, the flanking sequence may be synthesizedusing routine methods for nucleic acid synthesis or cloning.

Whether all or only a portion of the flanking sequence is known, it maybe obtained using polymerase chain reaction (PCR) and/or by screening agenomic library with a suitable probe such as an oligonucleotide and/orflanking sequence fragment from the same or another species. Where theflanking sequence is not known, a fragment of DNA containing a flankingsequence may be isolated from a larger piece of DNA that may contain,for example, a coding sequence or even another gene or genes. Isolationmay be accomplished by restriction endonuclease digestion to produce theproper DNA fragment followed by isolation using agarose gelpurification, Qiagen® column chromatography (Chatsworth, Calif.), orother methods known to the skilled artisan. The selection of suitableenzymes to accomplish this purpose will be readily apparent to one ofordinary skill in the art.

An origin of replication is typically a part of those prokaryoticexpression vectors purchased commercially, and the origin aids in theamplification of the vector in a host cell. If the vector of choice doesnot contain an origin of replication site, one may be chemicallysynthesized based on a known sequence, and ligated into the vector. Forexample, the origin of replication from the plasmid pBR322 (New EnglandBiolabs, Beverly, Mass.) is suitable for most gram-negative bacteria,and various viral origins (e.g., SV40, polyoma, adenovirus, vesicularstomatitus virus (VSV), or papillomaviruses such as HPV or BPV) areuseful for cloning vectors in mammalian cells. Generally, the origin ofreplication component is not needed for mammalian expression vectors(for example, the SV40 origin is often used only because it alsocontains the virus early promoter).

A transcription termination sequence is typically located 3′ to the endof a polypeptide coding region and serves to terminate transcription.Usually, a transcription termination sequence in prokaryotic cells is aG-C rich fragment followed by a poly-T sequence. While the sequence iseasily cloned from a library or even purchased commercially as part of avector, it can also be readily synthesized using known methods fornucleic acid synthesis.

A selectable marker gene encodes a protein necessary for the survivaland growth of a host cell grown in a selective culture medium. Typicalselection marker genes encode proteins that (a) confer resistance toantibiotics or other toxins, e.g., ampicillin, tetracycline, orkanamycin for prokaryotic host cells; (b) complement auxotrophicdeficiencies of the cell; or (c) supply critical nutrients not availablefrom complex or defined media. Specific selectable markers are thekanamycin resistance gene, the ampicillin resistance gene, and thetetracycline resistance gene. Advantageously, a neomycin resistance genemay also be used for selection in both prokaryotic and eukaryotic hostcells.

Other selectable genes may be used to amplify the gene that will beexpressed. Amplification is the process wherein genes that are requiredfor production of a protein critical for growth or cell survival arereiterated in tandem within the chromosomes of successive generations ofrecombinant cells. Examples of suitable selectable markers for mammaliancells include dihydrofolate reductase (DHFR) and promoterless thymidinekinase genes. Mammalian cell transformants are placed under selectionpressure wherein only the transformants are uniquely adapted to surviveby virtue of the selectable gene present in the vector. Selectionpressure is imposed by culturing the transformed cells under conditionsin which the concentration of selection agent in the medium issuccessively increased, thereby leading to the amplification of both theselectable gene and the DNA that encodes another gene, such as one ormore components of the bispecific antigen binding proteins describedherein. As a result, increased quantities of a polypeptide aresynthesized from the amplified DNA.

A ribosome-binding site is usually necessary for translation initiationof mRNA and is characterized by a Shine-Dalgarno sequence (prokaryotes)or a Kozak sequence (eukaryotes). The element is typically located 3′ tothe promoter and 5′ to the coding sequence of the polypeptide to beexpressed. In certain embodiments, one or more coding regions may beoperably linked to an internal ribosome binding site (IRES), allowingtranslation of two open reading frames from a single RNA transcript.

In some cases, such as where glycosylation is desired in a eukaryotichost cell expression system, one may manipulate the various pre- orprosequences to improve glycosylation or yield. For example, one mayalter the peptidase cleavage site of a particular signal peptide, or addprosequences, which also may affect glycosylation. The final proteinproduct may have, in the −1 position (relative to the first amino acidof the mature protein) one or more additional amino acids incident toexpression, which may not have been totally removed. For example, thefinal protein product may have one or two amino acid residues found inthe peptidase cleavage site, attached to the amino-terminus.Alternatively, use of some enzyme cleavage sites may result in aslightly truncated form of the desired polypeptide, if the enzyme cutsat such area within the mature polypeptide.

Expression and cloning vectors of the invention will typically contain apromoter that is recognized by the host organism and operably linked tothe molecule encoding the polypeptide. The term “operably linked” asused herein refers to the linkage of two or more nucleic acid sequencesin such a manner that a nucleic acid molecule capable of directing thetranscription of a given gene and/or the synthesis of a desired proteinmolecule is produced. For example, a control sequence in a vector thatis “operably linked” to a protein coding sequence is ligated thereto sothat expression of the protein coding sequence is achieved underconditions compatible with the transcriptional activity of the controlsequences. More specifically, a promoter and/or enhancer sequence,including any combination of cis-acting transcriptional control elementsis operably linked to a coding sequence if it stimulates or modulatesthe transcription of the coding sequence in an appropriate host cell orother expression system.

Promoters are untranscribed sequences located upstream (i.e., 5′) to thestart codon of a structural gene (generally within about 100 to 1000 bp)that control transcription of the structural gene. Promoters areconventionally grouped into one of two classes: inducible promoters andconstitutive promoters. Inducible promoters initiate increased levels oftranscription from DNA under their control in response to some change inculture conditions, such as the presence or absence of a nutrient or achange in temperature. Constitutive promoters, on the other hand,uniformly transcribe a gene to which they are operably linked, that is,with little or no control over gene expression. A large number ofpromoters, recognized by a variety of potential host cells, are wellknown. A suitable promoter is operably linked to the DNA encoding e.g.,heavy chain, light chain, modified heavy chain, or other component ofthe bispecific antigen binding proteins of the invention, by removingthe promoter from the source DNA by restriction enzyme digestion andinserting the desired promoter sequence into the vector.

Suitable promoters for use with yeast hosts are also well known in theart. Yeast enhancers are advantageously used with yeast promoters.Suitable promoters for use with mammalian host cells are well known andinclude, but are not limited to, those obtained from the genomes ofviruses such as polyoma virus, fowlpox virus, adenovirus (such asAdenovirus 2), bovine papilloma virus, avian sarcoma virus,cytomegalovirus, retroviruses, hepatitis-B virus and most preferablySimian Virus 40 (SV40). Other suitable mammalian promoters includeheterologous mammalian promoters, for example, heat-shock promoters andthe actin promoter.

Additional promoters which may be of interest include, but are notlimited to: SV40 early promoter (Benoist and Chambon, 1981, Nature290:304-310); CMV promoter (Thornsen et al., 1984, Proc. Natl. Acad.U.S.A. 81:659-663); the promoter contained in the 3′ long terminalrepeat of Rous sarcoma virus (Yamamoto et al., 1980, Cell 22:787-797);herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad.Sci. U.S.A. 78: 1444-1445); promoter and regulatory sequences from themetallothionine gene Prinster et al., 1982, Nature 296:39-42); andprokaryotic promoters such as the beta-lactamase promoter(Villa-Kamaroff et al., 1978, Proc. Natl. Acad. Sci. U.S.A.75:3727-3731); or the tac promoter (DeBoer et al., 1983, Proc. Natl.Acad. Sci. U.S.A. 80:21-25). Also of interest are the following animaltranscriptional control regions, which exhibit tissue specificity andhave been utilized in transgenic animals: the elastase I gene controlregion that is active in pancreatic acinar cells (Swift et al., 1984,Cell 38:639-646; Ornitz et al., 1986, Cold Spring Harbor Symp. Quant.Biol. 50:399-409; MacDonald, 1987, Hepatology 7:425-515); the insulingene control region that is active in pancreatic beta cells (Hanahan,1985, Nature 315: 115-122); the immunoglobulin gene control region thatis active in lymphoid cells (Grosschedl et al., 1984, Cell 38:647-658;Adames et al., 1985, Nature 318:533-538; Alexander et al., 1987, Mol.Cell. Biol. 7: 1436-1444); the mouse mammary tumor virus control regionthat is active in testicular, breast, lymphoid and mast cells (Leder etal., 1986, Cell 45:485-495); the albumin gene control region that isactive in liver (Pinkert et al., 1987, Genes and Devel. 1:268-276); thealpha-feto-protein gene control region that is active in liver (Krumlaufet al., 1985, Mol. Cell. Biol. 5: 1639-1648; Hammer et al., 1987,Science 253:53-58); the alpha 1-antitrypsin gene control region that isactive in liver (Kelsey et al., 1987, Genes and Devel. 1: 161-171); thebeta-globin gene control region that is active in myeloid cells (Mogramet al, 1985, Nature 315:338-340; Kollias et al, 1986, Cell 46:89-94);the myelin basic protein gene control region that is active inoligodendrocyte cells in the brain (Readhead et al., 1987, Cell48:703-712); the myosin light chain-2 gene control region that is activein skeletal muscle (Sani, 1985, Nature 314:283-286); and thegonadotropic releasing hormone gene control region that is active in thehypothalamus (Mason et al., 1986, Science 234: 1372-1378).

An enhancer sequence may be inserted into the vector to increasetranscription of DNA encoding a component of the bispecific antigenbinding proteins (e.g., light chain, heavy chain, modified heavy chain,Fd fragment) by higher eukaryotes. Enhancers are cis-acting elements ofDNA, usually about 10-300 bp in length, that act on the promoter toincrease transcription. Enhancers are relatively orientation andposition independent, having been found at positions both 5′ and 3′ tothe transcription unit. Several enhancer sequences available frommammalian genes are known (e.g., globin, elastase, albumin,alpha-feto-protein and insulin). Typically, however, an enhancer from avirus is used. The SV40 enhancer, the cytomegalovirus early promoterenhancer, the polyoma enhancer, and adenovirus enhancers known in theart are exemplary enhancing elements for the activation of eukaryoticpromoters. While an enhancer may be positioned in the vector either 5′or 3′ to a coding sequence, it is typically located at a site 5′ fromthe promoter. A sequence encoding an appropriate native or heterologoussignal sequence (leader sequence or signal peptide) can be incorporatedinto an expression vector, to promote extracellular secretion of theantibody. The choice of signal peptide or leader depends on the type ofhost cells in which the antibody is to be produced, and a heterologoussignal sequence can replace the native signal sequence. Examples ofsignal peptides are described above. Other signal peptides that arefunctional in mammalian host cells include the signal sequence forinterleukin-7 (IL-7) described in U.S. Pat. No. 4,965,195; the signalsequence for interleukin-2 receptor described in Cosman et al., 1984,Nature 312:768; the interleukin-4 receptor signal peptide described inEP Patent No. 0367 566; the type I interleukin-1 receptor signal peptidedescribed in U.S. Pat. No. 4,968,607; the type II interleukin-1 receptorsignal peptide described in EP Patent No. 0 460 846.

The expression vectors that are provided may be constructed from astarting vector such as a commercially available vector. Such vectorsmay or may not contain all of the desired flanking sequences. Where oneor more of the flanking sequences described herein are not alreadypresent in the vector, they may be individually obtained and ligatedinto the vector. Methods used for obtaining each of the flankingsequences are well known to one skilled in the art. The expressionvectors can be introduced into host cells to thereby produce proteins,including fusion proteins, encoded by nucleic acids as described herein.

In certain embodiments, nucleic acids encoding the different componentsof the bispecific antigen binding proteins of the invention may beinserted into the same expression vector. For instance, the nucleic acidencoding an anti-PAC1 receptor light chain can be cloned into the samevector as the nucleic acid encoding an anti-PAC1 receptor heavy chain.In such embodiments, the two nucleic acids may be separated by aninternal ribosome entry site (IRES) and under the control of a singlepromoter such that the light chain and heavy chain are expressed fromthe same mRNA transcript. Alternatively, the two nucleic acids may beunder the control of two separate promoters such that the light chainand heavy chain are expressed from two separate mRNA transcripts. Insome embodiments, nucleic acids encoding the anti-PAC1 receptor lightchain and heavy chain are cloned into one expression vector and thenucleic acids encoding the anti-CGRP receptor light chain and heavychain are cloned into a second expression vector.

Similarly, for IgG-scFv bispecific antigen binding proteins, the nucleicacid encoding the light chain may be cloned into the same expressionvector as the nucleic acid encoding the modified heavy chain (fusionprotein comprising the heavy chain and scFv) where the two nucleic acidsare under the control of a single promoter and separated by an IRES orwhere the two nucleic acids are under the control of two separatepromoters. For IgG-Fab bispecific antigen binding proteins, nucleicacids encoding each of the three components may be cloned into the sameexpression vector. In some embodiments, the nucleic acid encoding thelight chain of the IgG-Fab molecule and the nucleic acid encoding thesecond polypeptide (which comprises the other half of the C-terminal Fabdomain) are cloned into one expression vector, whereas the nucleic acidencoding the modified heavy chain (fusion protein comprising a heavychain and half of a Fab domain) is cloned into a second expressionvector. In certain embodiments, all components of the bispecific antigenbinding proteins described herein are expressed from the same host cellpopulation. For example, even if one or more components is cloned into aseparate expression vector, the host cell is co-transfected with bothexpression vectors such that one cell produces all components of thebispecific antigen binding proteins.

After the vector has been constructed and the one or more nucleic acidmolecules encoding the components of the bispecific antigen bindingproteins described herein has been inserted into the proper site(s) ofthe vector or vectors, the completed vector(s) may be inserted into asuitable host cell for amplification and/or polypeptide expression.Thus, the present invention encompasses an isolated host cell comprisingone or more expression vectors encoding the components of the bispecificantigen binding proteins. The term “host cell” as used herein refers toa cell that has been transformed, or is capable of being transformed,with a nucleic acid and thereby expresses a gene of interest. The termincludes the progeny of the parent cell, whether or not the progeny isidentical in morphology or in genetic make-up to the original parentcell, so long as the gene of interest is present. A host cell thatcomprises an isolated nucleic acid of the invention, preferably operablylinked to at least one expression control sequence (e.g. promoter orenhancer), is a “recombinant host cell.”

The transformation of an expression vector for an antigen bindingprotein into a selected host cell may be accomplished by well-knownmethods including transfection, infection, calcium phosphateco-precipitation, electroporation, microinjection, lipofection,DEAE-dextran mediated transfection, or other known techniques. Themethod selected will in part be a function of the type of host cell tobe used. These methods and other suitable methods are well known to theskilled artisan, and are set forth, for example, in Sambrook et al.,2001, supra.

A host cell, when cultured under appropriate conditions, synthesizes anantigen binding protein that can subsequently be collected from theculture medium (if the host cell secretes it into the medium) ordirectly from the host cell producing it (if it is not secreted). Theselection of an appropriate host cell will depend upon various factors,such as desired expression levels, polypeptide modifications that aredesirable or necessary for activity (such as glycosylation orphosphorylation) and ease of folding into a biologically activemolecule.

Exemplary host cells include prokaryote, yeast, or higher eukaryotecells. Prokaryotic host cells include eubacteria, such as Gram-negativeor Gram-positive organisms, for example, Enterobacteriaceae such asEscherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus,Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratiamarcescans, and Shigella, as well as Bacillus, such as B. subtilis andB. licheniformis, Pseudomonas, and Streptomyces. Eukaryotic microbessuch as filamentous fungi or yeast are suitable cloning or expressionhosts for recombinant polypeptides. Saccharomyces cerevisiae, or commonbaker's yeast, is the most commonly used among lower eukaryotic hostmicroorganisms. However, a number of other genera, species, and strainsare commonly available and useful herein, such as Pichia, e.g. P.pastoris, Schizosaccharomyces pombe; Kluyveromyces, Yarrowia; Candida;Trichoderma reesia; Neurospora crassa; Schwanniomyces, such asSchwanniomyces occidentalis; and filamentous fungi, such as, e.g.,Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts such as A.nidulans and A. niger.

Host cells for the expression of glycosylated antigen binding proteinscan be derived from multicellular organisms. Examples of invertebratecells include plant and insect cells. Numerous baculoviral strains andvariants and corresponding permissive insect host cells from hosts suchas Spodoptera frugiperda (caterpillar), Aedes aegypti (mosquito), Aedesalbopictus (mosquito), Drosophila melanogaster (fruitfly), and Bombyxmori have been identified. A variety of viral strains for transfectionof such cells are publicly available, e.g., the L-1 variant ofAutographa californica NPV and the Bm-5 strain of Bombyx mori NPV.

Vertebrate host cells are also suitable hosts, and recombinantproduction of antigen binding proteins from such cells has becomeroutine procedure. Mammalian cell lines available as hosts forexpression are well known in the art and include, but are not limitedto, immortalized cell lines available from the American Type CultureCollection (ATCC), including but not limited to Chinese hamster ovary(CHO) cells, including CHOK1 cells (ATCC CCL61), DXB-11, DG-44, andChinese hamster ovary cells/-DHFR (CHO, Urlaub et al., Proc. Natl. Acad.Sci. USA 77: 4216, 1980); monkey kidney CV1 line transformed by SV40(COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cellssubcloned for growth in suspension culture, (Graham et al., J. GenVirol. 36: 59, 1977); baby hamster kidney cells (BHK, ATCC CCL 10);mouse sertoli cells (TM4, Mather, Biol. Reprod. 23: 243-251, 1980);monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells(VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells(BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); humanhepatoma cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCCCCL51); TRI cells (Mather et al., Annals N.Y Acad. Sci. 383: 44-68,1982); MRC 5 cells or FS4 cells; mammalian myeloma cells, and a numberof other cell lines. In certain embodiments, cell lines may be selectedthrough determining which cell lines have high expression levels andconstitutively produce bispecific antigen binding proteins with CGRPreceptor and PAC1 receptor binding properties. In another embodiment, acell line from the B cell lineage that does not make its own antibodybut has a capacity to make and secrete a heterologous antibody can beselected. CHO cells are preferred host cells in some embodiments forexpressing the bispecific antigen binding proteins of the invention.

Host cells are transformed or transfected with the above-describednucleic acids or vectors for production of bispecific antigen bindingproteins and are cultured in conventional nutrient media modified asappropriate for inducing promoters, selecting transformants, oramplifying the genes encoding the desired sequences. In addition, novelvectors and transfected cell lines with multiple copies of transcriptionunits separated by a selective marker are particularly useful for theexpression of antigen binding proteins. Thus, the present invention alsoprovides a method for preparing a bispecific antigen binding proteindescribed herein comprising culturing a host cell comprising one or moreexpression vectors described herein in a culture medium under conditionspermitting expression of the bispecific antigen binding protein encodedby the one or more expression vectors; and recovering the bispecificantigen binding protein from the culture medium.

The host cells used to produce the antigen binding proteins of theinvention may be cultured in a variety of media. Commercially availablemedia such as Ham's F10 (Sigma), Minimal Essential Medium ((MEM),(Sigma), RPMI-1640 (Sigma), and Dulbecco's Modified Eagle's Medium((DMEM), Sigma) are suitable for culturing the host cells. In addition,any of the media described in Ham et al., Meth. Enz. 58: 44, 1979;Barnes et al., Anal. Biochem. 102: 255, 1980; U.S. Pat. Nos. 4,767,704;4,657,866; 4,927,762; 4,560,655; or 5,122,469; WO90103430; WO 87/00195;or U.S. Pat. Re. No. 30,985 may be used as culture media for the hostcells. Any of these media may be supplemented as necessary with hormonesand/or other growth factors (such as insulin, transferrin, or epidermalgrowth factor), salts (such as sodium chloride, calcium, magnesium, andphosphate), buffers (such as HEPES), nucleotides (such as adenosine andthymidine), antibiotics (such as Gentamycin™ drug), trace elements(defined as inorganic compounds usually present at final concentrationsin the micromolar range), and glucose or an equivalent energy source.Any other necessary supplements may also be included at appropriateconcentrations that would be known to those skilled in the art. Theculture conditions, such as temperature, pH, and the like, are thosepreviously used with the host cell selected for expression, and will beapparent to the ordinarily skilled artisan.

Upon culturing the host cells, the bispecific antigen binding proteincan be produced intracellularly, in the periplasmic space, or directlysecreted into the medium. If the antigen binding protein is producedintracellularly, as a first step, the particulate debris, either hostcells or lysed fragments, is removed, for example, by centrifugation orultrafiltration. The bispecifc antigen binding protein can be purifiedusing, for example, hydroxyapatite chromatography, cation or anionexchange chromatography, or preferably affinity chromatography, usingthe antigen(s) of interest or protein A or protein G as an affinityligand. Protein A can be used to purify proteins that includepolypeptides that are based on human γ1, γ2, or γ4 heavy chains(Lindmark et al., J. Immunol. Meth. 62: 1-13, 1983). Protein G isrecommended for all mouse isotypes and for human γ3 (Guss et al., EMBOJ. 5: 15671575, 1986). The matrix to which the affinity ligand isattached is most often agarose, but other matrices are available.Mechanically stable matrices such as controlled pore glass orpoly(styrenedivinyl)benzene allow for faster flow rates and shorterprocessing times than can be achieved with agarose. Where the proteincomprises a CH3 domain, the Bakerbond ABX™ resin (J. T. Baker,Phillipsburg, N.J.) is useful for purification. Other techniques forprotein purification such as ethanol precipitation, Reverse Phase HPLC,chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are alsopossible depending on the particular bispecific antigen binding proteinto be recovered.

In some embodiments, the invention provides a pharmaceutical compositioncomprising one or a plurality of the bispecific antigen binding proteinsof the invention together with pharmaceutically acceptable diluents,carriers, excipients, solubilizers, emulsifiers, preservatives, and/oradjuvants. Pharmaceutical compositions of the invention include, but arenot limited to, liquid, frozen, and lyophilized compositions.“Pharmaceutically-acceptable” refers to molecules, compounds, andcompositions that are non-toxic to human recipients at the dosages andconcentrations employed and/or do not produce allergic or adversereactions when administered to humans. In certain embodiments, thepharmaceutical composition may contain formulation materials formodifying, maintaining or preserving, for example, the pH, osmolarity,viscosity, clarity, color, isotonicity, odor, sterility, stability, rateof dissolution or release, adsorption or penetration of the composition.In such embodiments, suitable formulation materials include, but are notlimited to, amino acids (such as glycine, glutamine, asparagine,arginine or lysine); antimicrobials; antioxidants (such as ascorbicacid, sodium sulfite or sodium hydrogen-sulfite); buffers (such asborate, bicarbonate, Tris-HCl, citrates, phosphates or other organicacids); bulking agents (such as mannitol or glycine); chelating agents(such as ethylenediamine tetraacetic acid (EDTA)); complexing agents(such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin orhydroxypropyl-beta-cyclodextrin); fillers; monosaccharides;disaccharides; and other carbohydrates (such as glucose, mannose ordextrins); proteins (such as serum albumin, gelatin or immunoglobulins);coloring, flavoring and diluting agents; emulsifying agents; hydrophilicpolymers (such as polyvinylpyrrolidone); low molecular weightpolypeptides; salt-forming counterions (such as sodium); preservatives(such as benzalkonium chloride, benzoic acid, salicylic acid,thimerosal, phenethyl alcohol, methylparaben, propylparaben,chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such asglycerin, propylene glycol or polyethylene glycol); sugar alcohols (suchas mannitol or sorbitol); suspending agents; surfactants or wettingagents (such as pluronics, PEG, sorbitan esters, polysorbates such aspolysorbate 20, polysorbate 80, triton, tromethamine, lecithin,cholesterol, tyloxapal); stability enhancing agents (such as sucrose orsorbitol); tonicity enhancing agents (such as alkali metal halides,preferably sodium or potassium chloride, mannitol sorbitol); deliveryvehicles; diluents; excipients and/or pharmaceutical adjuvants. Methodsand suitable materials for formulating molecules for therapeutic use areknown in the pharmaceutical arts, and are described, for example, inREMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, (A. R. Genrmo, ed.),1990, Mack Publishing Company.

In some embodiments, the pharmaceutical composition of the inventioncomprises a standard pharmaceutical carrier, such as a sterile phosphatebuffered saline solution, bacteriostatic water, and the like. A varietyof aqueous carriers may be used, e.g., water, buffered water, 0.4%saline, 0.3% glycine and the like, and may include other proteins forenhanced stability, such as albumin, lipoprotein, globulin, etc.,subjected to mild chemical modifications or the like.

Exemplary concentrations of the bispecific antigen binding proteins inthe formulation may range from about 0.1 mg/ml to about 180 mg/ml orfrom about 0.1 mg/mL to about 50 mg/mL, or from about 0.5 mg/mL to about25 mg/mL, or alternatively from about 2 mg/mL to about 10 mg/mL. Anaqueous formulation of the antigen binding protein may be prepared in apH-buffered solution, for example, at pH ranging from about 4.5 to about6.5, or from about 4.8 to about 5.5, or alternatively about 5.0.Examples of buffers that are suitable for a pH within this range includeacetate (e.g. sodium acetate), succinate (such as sodium succinate),gluconate, histidine, citrate and other organic acid buffers. The bufferconcentration can be from about 1 mM to about 200 mM, or from about 10mM to about 60 mM, depending, for example, on the buffer and the desiredisotonicity of the formulation.

A tonicity agent, which may also stabilize the antigen binding protein,may be included in the formulation. Exemplary tonicity agents includepolyols, such as mannitol, sucrose or trehalose. Preferably the aqueousformulation is isotonic, although hypertonic or hypotonic solutions maybe suitable. Exemplary concentrations of the polyol in the formulationmay range from about 1% to about 15% w/v.

A surfactant may also be added to the antigen binding proteinformulation to reduce aggregation of the formulated antigen bindingprotein and/or minimize the formation of particulates in the formulationand/or reduce adsorption. Exemplary surfactants include nonionicsurfactants such as polysorbates (e.g. polysorbate 20 or polysorbate 80)or poloxamers (e.g. poloxamer 188). Exemplary concentrations ofsurfactant may range from about 0.001% to about 0.5%, or from about0.005% to about 0.2%, or alternatively from about 0.004% to about 0.01%w/v.

In one embodiment, the formulation contains the above-identified agents(i.e. antigen binding protein, buffer, polyol and surfactant) and isessentially free of one or more preservatives, such as benzyl alcohol,phenol, m-cresol, chlorobutanol and benzethonium chloride. In anotherembodiment, a preservative may be included in the formulation, e.g., atconcentrations ranging from about 0.1% to about 2%, or alternativelyfrom about 0.5% to about 1%. One or more other pharmaceuticallyacceptable carriers, excipients or stabilizers such as those describedin Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)may be included in the formulation provided that they do not adverselyaffect the desired characteristics of the formulation.

Therapeutic formulations of the bispecific antigen binding protein areprepared for storage by mixing the bispecific antigen binding proteinhaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the formof lyophilized formulations or aqueous solutions. Acceptable carriers,excipients, or stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrate,and other organic acids; antioxidants including ascorbic acid andmethionine; preservatives (such as octadecyldimethylbenzyl ammoniumchloride; hexamethonium chloride; benzalkonium chloride, benzethoniumchloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methylor propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; andm-cresol); low molecular weight (less than about 10 residues)polypeptides; proteins, such as serum albumin, gelatin, orimmunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;amino acids such as glycine, glutamine, asparagine, histidine, arginine,or lysine; monosaccharides, disaccharides, and other carbohydratesincluding glucose, mannose, maltose, or dextrins; chelating agents suchas EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol;salt-forming counter-ions such as sodium; metal complexes (e.g.,Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™,PLURONICS™ or polyethylene glycol (PEG).

In one embodiment, a suitable formulation of the claimed inventioncontains an isotonic buffer such as a phosphate, acetate, or TRIS bufferin combination with a tonicity agent, such as a polyol, sorbitol,sucrose or sodium chloride, which tonicifies and stabilizes. One exampleof such a tonicity agent is 5% sorbitol or sucrose. In addition, theformulation could optionally include a surfactant at 0.01% to 0.02%wt/vol, for example, to prevent aggregation or improve stability. The pHof the formulation may range from 4.5-6.5 or 4.5 to 5.5. Other exemplarydescriptions of pharmaceutical formulations for antigen binding proteinsmay be found in US 2003/0113316 and U.S. Pat. No. 6,171,586, eachincorporated herein by reference in its entirety.

The formulation herein may also contain more than one active compound asnecessary for the particular indication being treated, preferably thosewith complementary activities that do not adversely affect each other.For example, it may be desirable to further provide an immunosuppressiveagent. Such molecules are suitably present in combination in amountsthat are effective for the purpose intended.

The active ingredients may also be entrapped in microcapsule prepared,for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsule and poly-(methylmethacylate) microcapsule,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Suspensions and crystal forms of antigen binding proteins are alsocontemplated. Methods to make suspensions and crystal forms are known toone of skill in the art.

The formulations to be used for in vivo administration must be sterile.The compositions of the invention may be sterilized by conventional,well known sterilization techniques. For example, sterilization isreadily accomplished by filtration through sterile filtration membranes.The resulting solutions may be packaged for use or filtered underaseptic conditions and lyophilized, the lyophilized preparation beingcombined with a sterile solution prior to administration.

The process of freeze-drying is often employed to stabilize polypeptidesfor long-term storage, particularly when the polypeptide is relativelyunstable in liquid compositions. A lyophilization cycle is usuallycomposed of three steps: freezing, primary drying, and secondary drying(see Williams and Polli, Journal of Parenteral Science and Technology,Volume 38, Number 2, pages 48-59, 1984). In the freezing step, thesolution is cooled until it is adequately frozen. Bulk water in thesolution forms ice at this stage. The ice sublimes in the primary dryingstage, which is conducted by reducing chamber pressure below the vaporpressure of the ice, using a vacuum. Finally, sorbed or bound water isremoved at the secondary drying stage under reduced chamber pressure andan elevated shelf temperature. The process produces a material known asa lyophilized cake. Thereafter the cake can be reconstituted prior touse.

The standard reconstitution practice for lyophilized material is to addback a volume of pure water (typically equivalent to the volume removedduring lyophilization), although dilute solutions of antibacterialagents are sometimes used in the production of pharmaceuticals forparenteral administration (see Chen, Drug Development and IndustrialPharmacy, Volume 18: 1311-1354, 1992).

Excipients have been noted in some cases to act as stabilizers forfreeze-dried products (see Carpenter et al., Volume 74: 225-239, 1991).For example, known excipients include polyols (including mannitol,sorbitol and glycerol); sugars (including glucose and sucrose); andamino acids (including alanine, glycine and glutamic acid).

In addition, polyols and sugars are also often used to protectpolypeptides from freezing and drying-induced damage and to enhance thestability during storage in the dried state. In general, sugars, inparticular disaccharides, are effective in both the freeze-dryingprocess and during storage. Other classes of molecules, including mono-and di-saccharides and polymers such as PVP, have also been reported asstabilizers of lyophilized products.

For injection, the pharmaceutical formulation and/or medicament may be apowder suitable for reconstitution with an appropriate solution asdescribed above. Examples of these include, but are not limited to,freeze dried, rotary dried or spray dried powders, amorphous powders,granules, precipitates, or particulates. For injection, the formulationsmay optionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the bispecific antigen binding protein,which matrices are in the form of shaped articles, e.g., films, ormicrocapsule. Examples of sustained-release matrices include polyesters,hydrogels (for example, poly(2-hydroxyethyl-methacrylate), orpoly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymersof L-glutamic acid and y ethyl-L-glutamate, non-degradableethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymerssuch as the Lupron Depot™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate), andpoly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinylacetate and lactic acid-glycolic acid enable release of molecules forover 100 days, certain hydrogels release proteins for shorter timeperiods. When encapsulated polypeptides remain in the body for a longtime, they may denature or aggregate as a result of exposure to moistureat 37° C., resulting in a loss of biological activity and possiblechanges in immunogenicity. Rational strategies can be devised forstabilization depending on the mechanism involved. For example, if theaggregation mechanism is discovered to be intermolecular S—S bondformation through thio-disulfide interchange, stabilization may beachieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

The formulations of the invention may be designed to be short-acting,fast-releasing, long-acting, or sustained-releasing as described herein.Thus, the pharmaceutical formulations may also be formulated forcontrolled release or for slow release.

Specific dosages may be adjusted depending on conditions of disease, theage, body weight, general health conditions, sex, and diet of thesubject, dose intervals, administration routes, excretion rate, andcombinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant invention.

The bispecific antigen binding protein is administered by any suitablemeans, including parenteral, subcutaneous, intraperitoneal,intrapulmonary, and intranasal, and, if desired for local treatment,intralesional administration. Parenteral infusions include intravenous,intraarterial, intraperitoneal, intramuscular, intradermal orsubcutaneous administration. In addition, the bispecific antigen bindingprotein is suitably administered by pulse infusion, particularly withdeclining doses of the antigen binding protein. Preferably the dosing isgiven by injections, most preferably intravenous or subcutaneousinjections, depending in part on whether the administration is brief orchronic. Other administration methods are contemplated, includingtopical, particularly transdermal, transmucosal, rectal, oral or localadministration e.g. through a catheter placed close to the desired site.Most preferably, the antigen binding protein of the invention isadministered intravenously in a physiological solution at a dose rangingbetween 0.01 mg/kg to 100 mg/kg at a frequency ranging from daily toweekly to monthly (e.g. every day, every other day, every third day, or2, 3, 4, 5, or 6 times per week), preferably a dose ranging from 0.1 to45 mg/kg, 0.1 to 15 mg/kg or 0.1 to 10 mg/kg at a frequency of once perweek, once every two weeks, or once a month.

The bispecific antigen binding proteins described herein are useful fortreating or ameliorating a condition associated with CGRP receptorand/or PAC1 receptor in a patient in need thereof. As used herein, theterm “treating” or “treatment” is an intervention performed with theintention of preventing the development or altering the pathology of adisorder.

Accordingly, “treatment” refers to both therapeutic treatment andprophylactic or preventative measures. Those in need of treatmentinclude those already diagnosed with or suffering from the disorder orcondition as well as those in which the disorder or condition is to beprevented. “Treatment” includes any indicia of success in theamelioration of an injury, pathology or condition, including anyobjective or subjective parameter such as abatement, remission,diminishing of symptoms, or making the injury, pathology or conditionmore tolerable to the patient, slowing in the rate of degeneration ordecline, making the final point of degeneration less debilitating, orimproving a patient's physical or mental well-being. The treatment oramelioration of symptoms can be based on objective or subjectiveparameters, including the results of a physical examination,self-reporting by a patient, neuropsychiatric exams, and/or apsychiatric evaluation.

Accordingly, in some embodiments, the present invention provides amethod for treating or preventing a condition associated with CGRPreceptor and/or PAC1 receptor in a patient in need thereof, comprisingadministering to the patient an effective amount of a bispecific antigenbinding protein described herein. The term “patient” includes humanpatients. An “effective amount” is generally an amount sufficient toreduce the severity and/or frequency of symptoms, eliminate the symptomsand/or underlying cause, prevent the occurrence of symptoms and/or theirunderlying cause, and/or improve or remediate the damage that resultsfrom or is associated with a particular condition (e.g. chronic pain,headache or migraine). In some embodiments, the effective amount is atherapeutically effective amount or a prophylactically effective amount.A “therapeutically effective amount” is an amount sufficient to remedy adisease state (e.g., a headache, migraine, or chronic pain) orsymptom(s), particularly a state or symptom(s) associated with thedisease state, or otherwise prevent, hinder, retard or reverse theprogression of the disease state or any other undesirable symptomassociated with the disease in any way whatsoever (i.e. that provides“therapeutic efficacy”). A “prophylactically effective amount” is anamount of a pharmaceutical composition that, when administered to asubject, will have the intended prophylactic effect, e.g., preventing ordelaying the onset (or reoccurrence) of the condition (e.g. headache ormigraine), or reducing the likelihood of the onset (or reoccurrence) ofthe condition (e.g. headache, migraine, or headache symptoms). The fulltherapeutic or prophylactic effect does not necessarily occur byadministration of one dose, and may occur only after administration of aseries of doses. Thus, a therapeutically or prophylactically effectiveamount may be administered in one or more administrations.

In certain embodiments, the present invention provides a method fortreating or ameliorating headache, particularly migraine headache, in apatient in need thereof comprising administering to the patient aneffective amount of a bispecific antigen binding protein describedherein. Migraine headaches are recurrent headaches lasting about 4 toabout 72 hours that are characterized by unilateral, pulsating, and/ormoderate to severe pain and/or pain that is exacerbated by physicalactivity. Migraine headaches are often accompanied by nausea, vomiting,and/or sensitivity to light (photophobia), sound (phonophobia), orsmell. In some patients, an aura precedes the onset of the migraineheadache. The aura is typically a visual, sensory, language, or motordisturbance that signals the headache will soon occur. The methodsdescribed herein prevent, treat, or ameliorate one or more symptoms ofmigraine headaches with and without aura in human patients.

Activation of the CGRP receptor and PAC1 receptor by their respectiveligands induce vasodilation, particularly vasodilation of the duravasculature. Both receptor signaling cascades have been implicated inmigraine pathophysiology, and are believed to contribute to theinduction of migraine through different, but related mechanisms. CGRPreleased as a result of activation of the trigeminovascular system notonly induces vasodilation of the cranial vessels, but also contributesto the induction of neurogenic inflammation, which is a form ofinflammation secondary to sensory nerve activation. See, e.g., Bigal etal., Headache, Vol. 53(8):1230-44, 2013, which is hereby incorporated byreference. CGRP also acts as a neurotransmitter to transmit pain signalsfrom the brainstem to the thalamus. While CGRP acts through the sensorysystem, the PAC1 receptor and its PACAP ligand operate through theparasympathetic division of the autonomic nervous system.Immunohistochemistry studies in cynomolgus monkey mapped PACAP and PAC1localization to the parasympathetic pathway through the sphenopalatineganglion (SPG; also known as pterygopalatine ganglion), which alsoinnervates the dura vasculature (data not shown). The parasympatheticpathway is independent and parallel to the sensory pathway that alsocontrols the dura vasculature tone. Infusion of the PAC1 receptoragonist PACAP causes migraine-like headache in migraine patients,suggesting that blocking PAC1 may be useful for treating migraine(Schytz et al., Brain 132:16-25, 2009).

Additional experiments performed in support of the present inventionshowed that a selective PAC1 antibody blocked electrically stimulatedtrigeminal cervical complex (TCC) activation, an electrophysiology modelthat has been reported to correlate with clinical migraine efficacy(data not shown). In some embodiments, the bispecific antigen bindingproteins described herein have an additive or synergistic effect intreating migraine headache (e.g. reducing the frequency, duration, orseverity of migraine headache) as compared to the treatment effectobtained with either an anti-CGRP receptor antagonist or an anti-PAC1receptor antagonist alone. Without being bound by theory, it is believedthat inhibiting both the CGRP receptor and the PAC1 receptor with thebispecific antigen binding proteins of the invention will providegreater efficacy in treating migraine headache than antagonizing eithertarget alone.

In some embodiments, the patients to be treated according to the methodsof the invention have, suffer from, or are diagnosed with episodicmigraine. Episodic migraine is diagnosed when patients with a history ofmigraine (e.g. at least five lifetime attacks of migraine headache) have14 or fewer migraine headache days per month. A “migraine headache day”includes any calendar day during which a patient experiences the onset,continuation, or recurrence of a “migraine headache” with or withoutaura lasting greater than 30 minutes. A “migraine headache” is aheadache associated with nausea or vomiting or sensitivity to light orsound and/or a headache characterized by at least two of the followingpain features: unilateral pain, throbbing pain, moderate to severe painintensity, or pain exacerbated by physical activity.

In certain embodiments, patients having, suffering from, or diagnosedwith episodic migraine have at least four, but less than 15 migraineheadache days per month on average. In related embodiments, patientshaving, suffering from, or diagnosed with episodic migraine have fewerthan 15 headache days per month on average. As used herein, a “headacheday” is any calendar day in which the patient experiences a migraineheadache as defined herein or any headache that lasts greater than 30minutes or requires acute headache treatment.

In certain embodiments, the patients to be treated according to themethods of the invention have, suffer from, or are diagnosed withchronic migraine. Chronic migraine is diagnosed when migraine patients(i.e. patients with at least five lifetime attacks of migraine headache)have 15 or more headache days per month and at least 8 of the headachedays are migraine headache days. In some embodiments, patients having,suffering from, or diagnosed with chronic migraine have 15 or moremigraine headache days per month on average. In certain embodiments ofthe methods described herein, administration of a bispecific antigenbinding protein of the invention prevents, reduces, or delays theprogression of episodic migraine in the patient to chronic migraine.

In other embodiments, the present invention provides a method fortreating or ameliorating cluster headache in a patient in need thereofcomprising administering to the patient an effective amount of abispecific antigen binding protein described herein. Cluster headache isa condition that involves, as its most prominent feature, recurrent,severe headaches on one side of the head, typically around the eye (seeNesbitt et al., BMJ, Vol. 344:e2407, 2012). Some doctors and scientistshave described the pain resulting from cluster headaches as the mostintense pain a human can endure—worse than giving birth, burns or brokenbones. Cluster headaches often occur periodically: spontaneousremissions interrupt active periods of pain. Cluster headaches are oftenaccompanied by cranial autonomic symptoms, such as tearing, nasalcongestion, ptosis, pupil constriction, facial blushing, sweating, andswelling around the eye, often confined to the side of the head with thepain. The average age of onset of cluster headache is ˜30-50 years. Itis more prevalent in males with a male to female ratio of about 2.5:1 toabout 3.5:1. Sphenopalatine ganglion (SPG) stimulation has been used forthe treatment of cluster headache. A neurostimulation system, whichdelivers low-level (but high frequency, physiologic-blocking) electricalstimulation to the SPG, has demonstrated efficacy in relieving the acutedebilitating pain of cluster headache in a recent clinical trial (seeSchoenen J, et al., Cephalalgia, Vol. 33(10):816-30, 2013). In view ofthis evidence and because PACAP is one of the major neurotransmitters inSPG, inhibition of PAC1 receptor signaling with a bispecific antigenbinding protein described herein is expected to have efficacy intreating cluster headache in humans.

Other conditions associated with CGRP receptor and/or PAC1 receptorsignaling that may be treated according to the methods of the inventioninclude, but are not limited to, chronic pain syndromes, such asarthritic pain (e.g. osteoarthritis and rheumatoid arthritis),neurogenic inflammation, tension-type headaches, hemiplegic migraine,retinal migraine, and vasomotor symptoms (e.g. hot flashes, facialflushing, sweating, and night sweats), such as those associate withmenopause. In one embodiment, the condition is chronic pain. CGRP may beinvolved in chronic pain syndromes other than migraine. In rodents,intrathecally-delivered CGRP induces severe pain, and CGRP levels areenhanced in a number of pain models. In addition, CGRP antagonistspartially block nociception in acute pancreatitis in rodents (see Wicket al. Surgery, Volume 139: 197-201, 2006). In any of the methodsdescribed herein, the treatment can comprise prophylactic treatment.Prophylactic treatment refers to treatment designed to be taken beforethe onset of a condition or an attack (e.g. before a migraine attack oronset of a cluster headache episode) to reduce the frequency, severity,and/or length of the symptoms (e.g. migraine or cluster headaches) inthe patient.

The bispecific antigen binding proteins of the invention are useful fordetecting CGRP receptor and/or PAC1 receptor in biological samples andidentification of cells or tissues that express the CGRP receptor and/orPAC1 receptor. For instance, the bispecific antigen binding proteins canbe used in diagnostic assays, e.g., binding assays to detect and/orquantify CGRP receptor and/or PAC1 receptor expressed in a tissue orcell. In addition, the bispecific antigen binding proteins describedherein can be used to inhibit CGRP receptor from forming a complex withits ligand CGRP, thereby modulating the biological activity of CGRPreceptor in a cell or tissue. Likewise, the bispecific antigen bindingproteins described herein can be used to inhibit PAC1 receptor fromforming a complex with its ligand PACAP, thereby modulating thebiological activity of PAC1 receptor in a cell or tissue. Examples ofactivities that can be modulated include, but are not limited to,inhibiting vasodilation and/or reducing neurogenic inflammation.

The bispecific antigen binding proteins described herein can be used fordiagnostic purposes to detect, diagnose, or monitor diseases and/orconditions associated with the CGRP receptor and/or the PAC1 receptor.Also provided are methods for the detection of the presence of CGRPreceptor or PAC1 receptor in a sample using classical immunohistologicalmethods known to those of skill in the art (e.g., Tijssen, 1993,Practice and Theory of Enzyme Immunoassays, Vol 15 (Eds R. H. Burdon andP. H. van Knippenberg, Elsevier, Amsterdam); Zola, 1987, MonoclonalAntibodies: A Manual of Techniques, pp. 147-158 (CRC Press, Inc.);Jalkanen et al., 1985, J. Cell. Biol. 101:976-985; Jalkanen et al.,1987, J. Cell Biol. 105:3087-3096). The detection of either receptor(CGRP receptor or PAC1 receptor) can be performed in vivo or in vitro.

Diagnostic applications provided herein include use of the antigenbinding proteins to detect expression of CGRP receptor and/or PAC1receptor and binding of the ligands to either receptor. Examples ofmethods useful in the detection of the presence of the receptor includeimmunoassays, such as the enzyme linked immunosorbent assay (ELISA) andthe radioimmunoassay (RIA).

For diagnostic applications, the antigen binding protein typically willbe labeled with a detectable labeling group. Suitable labeling groupsinclude, but are not limited to, the following: radioisotopes orradionuclides (e.g., ³H, ¹⁴C, ¹⁵N, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I),fluorescent groups (e.g., FITC, rhodamine, lanthanide phosphors),enzymatic groups (e.g., horseradish peroxidase, 3-galactosidase,luciferase, alkaline phosphatase), chemiluminescent groups, biotinylgroups, or predetermined polypeptide epitopes recognized by a secondaryreporter (e.g., leucine zipper pair sequences, binding sites forsecondary antibodies, metal binding domains, epitope tags). In someembodiments, the labeling group is coupled to the antigen bindingprotein via spacer arms of various lengths to reduce potential sterichindrance. Various methods for labeling proteins are known in the artand may be used.

In another embodiment, the bispecific antigen binding protein describedherein can be used to identify a cell or cells that express CGRPreceptor and/or PAC1 receptor. In a specific embodiment, the antigenbinding protein is labeled with a labeling group and the binding of thelabeled antigen binding protein to CGRP receptor and/or PAC1 receptor isdetected. In a further specific embodiment, the binding of the antigenbinding protein to CGRP receptor and/or PAC1 receptor is detected invivo. In a further specific embodiment, the bispecific antigen bindingprotein is isolated and measured using techniques known in the art. See,for example, Harlow and Lane, 1988, Antibodies: A Laboratory Manual, NewYork: Cold Spring Harbor (ed. 1991 and periodic supplements); John E.Coligan, ed., 1993, Current Protocols In Immunology New York: John Wiley& Sons.

Another aspect provides for detecting the presence of a test moleculethat competes for binding to CGRP receptor and/or PAC1 receptor with theantigen binding proteins described herein. An example of one such assaywould involve detecting the amount of free antigen binding protein in asolution containing an amount of CGRP receptor and/or PAC1 receptor inthe presence or absence of the test molecule. An increase in the amountof free antigen binding protein (i.e., the antigen binding protein notbound to CGRP receptor and/or PAC1 receptor) would indicate that thetest molecule is capable of competing for CGRP receptor and/or PAC1receptor binding with the bispecific antigen binding protein. In oneembodiment, the antigen binding protein is labeled with a labelinggroup. Alternatively, the test molecule is labeled and the amount offree test molecule is monitored in the presence and absence of theantigen binding protein.

The following are additional embodiments of the invention for exemplarypurposes, and are not intended to be limiting in any way:

Embodiment 1

A bispecific antigen binding protein that specifically binds to humanCGRP receptor and human PAC1.

Embodiment 2

The bispecific antigen binding protein of Embodiment 1, wherein theantigen binding protein is an antibody or an antibody fragment.

Embodiment 3

The bispecific antigen binding protein of Embodiments 1-2, wherein theantigen binding protein is an antibody, or antibody fragment, comprisingall four of the variable domains found in an antibody selected from theantibodies designated iPS:326417, iPS:326626, iPS:326628, iPS:326631,iPS:326634, iPS:327870, iPS:327871, iPS:326645, iPS:326648, iPS:326651,iPS:326654, iPS:328000, iPS:328001, iPS:326661, iPS:326663, iPS:326666,iPS:326669, iPS:327017, iPS:327018, iPS:327019, iPS:327023, iPS:327024,iPS:327025, iPS:327026, iPS:327091, iPS:327092, iPS:327093, iPS:327094,iPS:326414, iPS:327102, iPS:327103, iPS:327104, iPS:327105, iPS:327106,iPS:327107, iPS:327108, iPS:327109, iPS:327110, iPS:327111, iPS:327112,iPS:327267, iPS:327268, iPS:327269, iPS:327270, iPS:327272, iPS:327273,iPS:327274, iPS:327275, iPS:327276, iPS:327277, iPS:327278, iPS:327279,iPS:327280, iPS:327281, iPS:327282, iPS:327283, iPS:327284, iPS:327285,iPS:327286, iPS:327287, iPS:327288, iPS:327289, iPS:327290, iPS:327291,iPS:327677, iPS:327678, iPS:327679, iPS:327680, iPS:327681, iPS:327682,iPS:327683, iPS:327684, iPS:327685, iPS:327686, iPS:327687, iPS:327688,iPS:327689, iPS:327690, iPS:327691, iPS:327693, iPS:327694, iPS:327696,iPS:327697, iPS:327698, iPS:327699, iPS:327700, iPS:327701, iPS:327702,iPS:327703, iPS:327704, iPS:327705, iPS:327706, iPS:327707, iPS:327708,iPS:327709, iPS:327710, iPS:327711, iPS:327712, iPS:327713, iPS:327714,iPS:327717, iPS:327718, iPS:327719, iPS:327721, iPS:327722, iPS:327724,iPS:327725, iPS:327726, iPS:327727, iPS:327728, iPS:327729, iPS:327730,iPS:327731, iPS:327732, iPS:327733, iPS:327734, iPS:327735, iPS:327736,iPS:327737, iPS:327738, iPS:327739, iPS:327740, iPS:327741, iPS:327742,iPS:327872, iPS:327874, iPS:327875, iPS:327876, iPS:327877, iPS:327878,iPS:327879, iPS:327880, iPS:327881, iPS:327882, iPS:327883, iPS:327884,iPS:327885, iPS:327886, iPS:327887, iPS:327888, iPS:327889, iPS:327890,iPS:327891, iPS:327892, iPS:327893, iPS:327894, iPS:327895, iPS:327896,iPS:327897, iPS:328031, iPS:328033, iPS:328034, iPS:328035, iPS:328036,iPS:328037, iPS:328038, iPS:328039, iPS:328040, iPS:328041, iPS:328042,iPS:328043, iPS:328044, iPS:328045, iPS:328046, iPS:328047, iPS:328048,iPS:328049, iPS:328050, and iPS:328051, as set forth herein.

Embodiment 4

The bispecific antigen binding protein of Embodiments 1-3, wherein theantigen binding protein is an antibody: (a) selected from the antibodiesdesignated iPS:326417, iPS:326626, iPS:326628, iPS:326631, iPS:326634,iPS:327870, iPS:327871, iPS:326645, iPS:326648, iPS:326651, iPS:326654,iPS:328000, iPS:328001, iPS:326661, iPS:326663, iPS:326666, iPS:326669,iPS:327017, iPS:327018, iPS:327019, iPS:327023, iPS:327024, iPS:327025,iPS:327026, iPS:327091, iPS:327092, iPS:327093, iPS:327094, iPS:326414,iPS:327102, iPS:327103, iPS:327104, iPS:327105, iPS:327106, iPS:327107,iPS:327108, iPS:327109, iPS:327110, iPS:327111, iPS:327112, iPS:327267,iPS:327268, iPS:327269, iPS:327270, iPS:327272, iPS:327273, iPS:327274,iPS:327275, iPS:327276, iPS:327277, iPS:327278, iPS:327279, iPS:327280,iPS:327281, iPS:327282, iPS:327283, iPS:327284, iPS:327285, iPS:327286,iPS:327287, iPS:327288, iPS:327289, iPS:327290, iPS:327291, iPS:327677,iPS:327678, iPS:327679, iPS:327680, iPS:327681, iPS:327682, iPS:327683,iPS:327684, iPS:327685, iPS:327686, iPS:327687, iPS:327688, iPS:327689,iPS:327690, iPS:327691, iPS:327693, iPS:327694, iPS:327696, iPS:327697,iPS:327698, iPS:327699, iPS:327700, iPS:327701, iPS:327702, iPS:327703,iPS:327704, iPS:327705, iPS:327706, iPS:327707, iPS:327708, iPS:327709,iPS:327710, iPS:327711, iPS:327712, iPS:327713, iPS:327714, iPS:327717,iPS:327718, iPS:327719, iPS:327721, iPS:327722, iPS:327724, iPS:327725,iPS:327726, iPS:327727, iPS:327728, iPS:327729, iPS:327730, iPS:327731,iPS:327732, iPS:327733, iPS:327734, iPS:327735, iPS:327736, iPS:327737,iPS:327738, iPS:327739, iPS:327740, iPS:327741, iPS:327742, iPS:327872,iPS:327874, iPS:327875, iPS:327876, iPS:327877, iPS:327878, iPS:327879,iPS:327880, iPS:327881, iPS:327882, iPS:327883, iPS:327884, iPS:327885,iPS:327886, iPS:327887, iPS:327888, iPS:327889, iPS:327890, iPS:327891,iPS:327892, iPS:327893, iPS:327894, iPS:327895, iPS:327896, iPS:327897,iPS:328031, iPS:328033, iPS:328034, iPS:328035, iPS:328036, iPS:328037,iPS:328038, iPS:328039, iPS:328040, iPS:328041, iPS:328042, iPS:328043,iPS:328044, iPS:328045, iPS:328046, iPS:328047, iPS:328048, iPS:328049,iPS:328050, and iPS:328051, as set forth herein, or (b) an antibody from(a) comprising an immunoglobulin light chain or immunoglobulin heavychain from which one, two, three, four or five amino acid residues arelacking from the N-terminal or C-terminal of said light chain or heavychain, or both.

Embodiment 5

The bispecific antigen binding protein of Embodiments 1-4, wherein theantigen binding protein is an antibody fragment selected from a Fab, aFab′, a F(ab′)₂, a Fv, a Fd, a domain antibody (dAb), a complementaritydetermining region (CDR) fragment, a single-chain antibody (scFv), asingle chain antibody fragment, a maxibody, a diabody, a triabody, atetrabody, a minibody, a linear antibody, a chelating recombinantantibody, an intrabody, a nanobody, a small modular immunopharmaceutical(SMIP), an antigen-binding-domain immunoglobulin fusion protein, and acamelized antibody.

Embodiment 6

The bispecific antigen binding protein of Embodiments 1-5, comprisingconstant regions of the IgG1, IgG2, IgG3, or IgG4 immunoglobulinisotype.

Embodiment 7

The bispecific antigen binding protein of Embodiments 1-6, comprisingall twelve complementarity determining regions (CDRs) of an antibodyselected from the antibodies designated iPS:326417, iPS:326626,iPS:326628, iPS:326631, iPS:326634, iPS:327870, iPS:327871, iPS:326645,iPS:326648, iPS:326651, iPS:326654, iPS:328000, iPS:328001, iPS:326661,iPS:326663, iPS:326666, iPS:326669, iPS:327017, iPS:327018, iPS:327019,iPS:327023, iPS:327024, iPS:327025, iPS:327026, iPS:327091, iPS:327092,iPS:327093, iPS:327094, iPS:326414, iPS:327102, iPS:327103, iPS:327104,iPS:327105, iPS:327106, iPS:327107, iPS:327108, iPS:327109, iPS:327110,iPS:327111, iPS:327112, iPS:327267, iPS:327268, iPS:327269, iPS:327270,iPS:327272, iPS:327273, iPS:327274, iPS:327275, iPS:327276, iPS:327277,iPS:327278, iPS:327279, iPS:327280, iPS:327281, iPS:327282, iPS:327283,iPS:327284, iPS:327285, iPS:327286, iPS:327287, iPS:327288, iPS:327289,iPS:327290, iPS:327291, iPS:327677, iPS:327678, iPS:327679, iPS:327680,iPS:327681, iPS:327682, iPS:327683, iPS:327684, iPS:327685, iPS:327686,iPS:327687, iPS:327688, iPS:327689, iPS:327690, iPS:327691, iPS:327693,iPS:327694, iPS:327696, iPS:327697, iPS:327698, iPS:327699, iPS:327700,iPS:327701, iPS:327702, iPS:327703, iPS:327704, iPS:327705, iPS:327706,iPS:327707, iPS:327708, iPS:327709, iPS:327710, iPS:327711, iPS:327712,iPS:327713, iPS:327714, iPS:327717, iPS:327718, iPS:327719, iPS:327721,iPS:327722, iPS:327724, iPS:327725, iPS:327726, iPS:327727, iPS:327728,iPS:327729, iPS:327730, iPS:327731, iPS:327732, iPS:327733, iPS:327734,iPS:327735, iPS:327736, iPS:327737, iPS:327738, iPS:327739, iPS:327740,iPS:327741, iPS:327742, iPS:327872, iPS:327874, iPS:327875, iPS:327876,iPS:327877, iPS:327878, iPS:327879, iPS:327880, iPS:327881, iPS:327882,iPS:327883, iPS:327884, iPS:327885, iPS:327886, iPS:327887, iPS:327888,iPS:327889, iPS:327890, iPS:327891, iPS:327892, iPS:327893, iPS:327894,iPS:327895, iPS:327896, iPS:327897, iPS:328031, iPS:328033, iPS:328034,iPS:328035, iPS:328036, iPS:328037, iPS:328038, iPS:328039, iPS:328040,iPS:328041, iPS:328042, iPS:328043, iPS:328044, iPS:328045, iPS:328046,iPS:328047, iPS:328048, iPS:328049, iPS:328050, and iPS:328051, as setforth herein.

Embodiment 8

The bispecific antigen binding protein of Embodiments 1-6, comprising:(a) all six complementarity determining regions (CDRs) that specificallybind CGRP receptor of an antibody selected from the antibodiesdesignated iPS:326417, iPS:326626, iPS:326628, iPS:326631, iPS:326634,iPS:327870, iPS:327871, iPS:326645, iPS:326648, iPS:326651, iPS:326654,iPS:328000, iPS:328001, iPS:326661, iPS:326663, iPS:326666, iPS:326669,iPS:327017, iPS:327018, iPS:327019, iPS:327023, iPS:327024, iPS:327025,iPS:327026, iPS:327091, iPS:327092, iPS:327093, iPS:327094, iPS:326414,iPS:327102, iPS:327103, iPS:327104, iPS:327105, iPS:327106, iPS:327107,iPS:327108, iPS:327109, iPS:327110, iPS:327111, iPS:327112, iPS:327267,iPS:327268, iPS:327269, iPS:327270, iPS:327272, iPS:327273, iPS:327274,iPS:327275, iPS:327276, iPS:327277, iPS:327278, iPS:327279, iPS:327280,iPS:327281, iPS:327282, iPS:327283, iPS:327284, iPS:327285, iPS:327286,iPS:327287, iPS:327288, iPS:327289, iPS:327290, iPS:327291, iPS:327677,iPS:327678, iPS:327679, iPS:327680, iPS:327681, iPS:327682, iPS:327683,iPS:327684, iPS:327685, iPS:327686, iPS:327687, iPS:327688, iPS:327689,iPS:327690, iPS:327691, iPS:327693, iPS:327694, iPS:327696, iPS:327697,iPS:327698, iPS:327699, iPS:327700, iPS:327701, iPS:327702, iPS:327703,iPS:327704, iPS:327705, iPS:327706, iPS:327707, iPS:327708, iPS:327709,iPS:327710, iPS:327711, iPS:327712, iPS:327713, iPS:327714, iPS:327717,iPS:327718, iPS:327719, iPS:327721, iPS:327722, iPS:327724, iPS:327725,iPS:327726, iPS:327727, iPS:327728, iPS:327729, iPS:327730, iPS:327731,iPS:327732, iPS:327733, iPS:327734, iPS:327735, iPS:327736, iPS:327737,iPS:327738, iPS:327739, iPS:327740, iPS:327741, iPS:327742, iPS:327872,iPS:327874, iPS:327875, iPS:327876, iPS:327877, iPS:327878, iPS:327879,iPS:327880, iPS:327881, iPS:327882, iPS:327883, iPS:327884, iPS:327885,iPS:327886, iPS:327887, iPS:327888, iPS:327889, iPS:327890, iPS:327891,iPS:327892, iPS:327893, iPS:327894, iPS:327895, iPS:327896, iPS:327897,iPS:328031, iPS:328033, iPS:328034, iPS:328035, iPS:328036, iPS:328037,iPS:328038, iPS:328039, iPS:328040, iPS:328041, iPS:328042, iPS:328043,iPS:328044, iPS:328045, iPS:328046, iPS:328047, iPS:328048, iPS:328049,iPS:328050, and iPS:328051, as set forth herein; and (b) all six CDRsthat specifically bind PAC1 from a different antibody selected from theantibodies designated iPS:326417, iPS:326626, iPS:326628, iPS:326631,iPS:326634, iPS:327870, iPS:327871, iPS:326645, iPS:326648, iPS:326651,iPS:326654, iPS:328000, iPS:328001, iPS:326661, iPS:326663, iPS:326666,iPS:326669, iPS:327017, iPS:327018, iPS:327019, iPS:327023, iPS:327024,iPS:327025, iPS:327026, iPS:327091, iPS:327092, iPS:327093, iPS:327094,iPS:326414, iPS:327102, iPS:327103, iPS:327104, iPS:327105, iPS:327106,iPS:327107, iPS:327108, iPS:327109, iPS:327110, iPS:327111, iPS:327112,iPS:327267, iPS:327268, iPS:327269, iPS:327270, iPS:327272, iPS:327273,iPS:327274, iPS:327275, iPS:327276, iPS:327277, iPS:327278, iPS:327279,iPS:327280, iPS:327281, iPS:327282, iPS:327283, iPS:327284, iPS:327285,iPS:327286, iPS:327287, iPS:327288, iPS:327289, iPS:327290, iPS:327291,iPS:327677, iPS:327678, iPS:327679, iPS:327680, iPS:327681, iPS:327682,iPS:327683, iPS:327684, iPS:327685, iPS:327686, iPS:327687, iPS:327688,iPS:327689, iPS:327690, iPS:327691, iPS:327693, iPS:327694, iPS:327696,iPS:327697, iPS:327698, iPS:327699, iPS:327700, iPS:327701, iPS:327702,iPS:327703, iPS:327704, iPS:327705, iPS:327706, iPS:327707, iPS:327708,iPS:327709, iPS:327710, iPS:327711, iPS:327712, iPS:327713, iPS:327714,iPS:327717, iPS:327718, iPS:327719, iPS:327721, iPS:327722, iPS:327724,iPS:327725, iPS:327726, iPS:327727, iPS:327728, iPS:327729, iPS:327730,iPS:327731, iPS:327732, iPS:327733, iPS:327734, iPS:327735, iPS:327736,iPS:327737, iPS:327738, iPS:327739, iPS:327740, iPS:327741, iPS:327742,iPS:327872, iPS:327874, iPS:327875, iPS:327876, iPS:327877, iPS:327878,iPS:327879, iPS:327880, iPS:327881, iPS:327882, iPS:327883, iPS:327884,iPS:327885, iPS:327886, iPS:327887, iPS:327888, iPS:327889, iPS:327890,iPS:327891, iPS:327892, iPS:327893, iPS:327894, iPS:327895, iPS:327896,iPS:327897, iPS:328031, iPS:328033, iPS:328034, iPS:328035, iPS:328036,iPS:328037, iPS:328038, iPS:328039, iPS:328040, iPS:328041, iPS:328042,iPS:328043, iPS:328044, iPS:328045, iPS:328046, iPS:328047, iPS:328048,iPS:328049, iPS:328050, and iPS:328051, as set forth herein.

Embodiment 9

The bispecific antigen binding protein of Embodiments 7-8, wherein oneor more of the CDRs of the antigen binding protein contains aconservative amino acid substitution.

Embodiment 10

The bispecific antigen binding protein of Embodiments 1-9, comprising amodification that reduces or eliminates effector function.

Embodiment 11

A pharmaceutical composition comprising the antigen binding protein ofany of Embodiments 1-10, and a pharmaceutically acceptable diluent,excipient or carrier.

Embodiment 12

A recombinant host cell that expresses the bispecific antigen bindingprotein of any of Embodiments 1-10.

Embodiment 13

The recombinant host cell of Embodiment 12, wherein the cell is a CHOcell.

Embodiment 14

A method for treating a condition associated with CGRP receptor or PAC1,or both, in a patient, comprising administering to a patient aneffective amount of the bispecific antigen binding protein of any ofEmbodiments 1-10.

Embodiment 15

The method of Embodiment 14, wherein the condition is headache.

Embodiment 16

The method of Embodiment 15, wherein the condition is a clusterheadache.

Embodiment 17

The method of Embodiment 15, wherein the condition is migraine.

Embodiment 18

The method of Embodiment 17, wherein the migraine is episodic migraine.

Embodiment 19

The method of Embodiment 17, wherein the migraine is chronic migraine.

Embodiment 20

The method of Embodiment 14, wherein the condition is chronic pain.

Embodiment 21

The method of any of Embodiments 14-20, wherein the method comprisesprophylactic treatment.

The following examples, including the experiments conducted and theresults achieved, are provided for illustrative purposes only and arenot to be construed as limiting the scope of the appended claims.

Examples Example 1. Engineering of CGRP Receptor and PAC1 ReceptorAntibodies to Improve Stability, Biophysical Properties, and Expression,and Eliminate Chemical Hotspots

Starting Antibodies

Generation and Screening of Anti-CGRP Receptor Antibodies.

Monoclonal anti-human CGRP receptor antibodies were generated andsequenced as described in Examples 1-3 of WO2010/075238 (Human CGRPReceptor Binding Proteins), which is hereby incorporated by reference inits entirety. Briefly, human CRLR cDNA (GenBank Accession No. U17473)and RAMP1 cDNA (GenBank Accession No. AJ001014) were cloned into themammalian cell expression vectors pcDNA3.1-Zeo and pcDNA3.1-Hyg(Invitrogen, Carlsbad, Calif.), respectively, for transfections of HEK293EBNA cells (Invitrogen). The hCRLR cDNA and hRAMP1 cDNA were alsocloned into the pDSRa24 vector (Kim, H. Y. et al. J. Inv. Derm. Symp.Proc. (2007) 12: 48-49) for transfections of AM-1 CHO cells (U.S. Pat.No. 6,210,924). Stable transfectants expressing CGRPR were identified.

XENOMOUSE® animals were immunized with purified soluble CGRP receptorprotein and purified CGRP receptor membranes prepared from AM-1 CHOcells stably expressing CGRP receptor, using doses of 10 Gg/mouse and150 Gg/mouse, respectively. Subsequent boosts were administered at dosesof 10 Gg/mouse of soluble CGRP receptor or 75 μg of purified CGRPreceptor membranes. XENOMOUSE® animals were also immunized with CGRPreceptor-expressing cells using doses of 3.4×10⁶ CGRPreceptor-transfected cells per mouse and subsequent boosts were of1.7×10⁶ CGRP receptor-transfected cells per mouse. Injection sites usedwere combinations of subcutaneous, base-of-tail, and intraperitoneal.Immunizations were performed in accordance with methods disclosed inU.S. Pat. No. 7,064,244, the disclosure of which is hereby incorporatedby reference. Adjuvants TiterMax Gold (Sigma; cat. # T2684), Alum (E.M.Sergent Pulp and Chemical Co., Clifton, N.J., cat. #1452-250) wereprepared according to manufacturers' instructions and mixed in a 1:1ratio of adjuvant emulsion to antigen solution. Sera were collected 4-6weeks after the first injection and specific titers were determined byFACs staining of recombinant CGRP receptor-expressing 293EBNA cells.Mice were immunized with either cells or membranes from cells expressingfull length CGRP receptor, or soluble CGRP receptor extracellulardomain, with a range of 11-17 immunizations over a period ofapproximately one to three and one-half months. Mice with the highestsera titer were identified and prepared for hybridoma generation. Theimmunizations were performed in groups of multiple mice, typically ten.Popliteal and inguinal lymph nodes and spleen tissues were typicallypooled from each group for generating hybridomas. Hybridoma supernatantswere screened for CGRP receptor-specific monoclonal antibodies byFluorometric Microvolume Assay Technology (FMAT) (Applied Biosystems,Foster City, Calif.). The supernatants were screened against either theAM-1 CHO huCGRP receptor cells or recombinant HEK 293 cells that weretransfected with human CGRP receptor and counter-screened againstparental HEK293 cells. Anti-CGRP receptor antibodies were sequencedusing standard RT-PCR methods, as described in Examples 2-3 ofWO2010/075238 (Human CGRP Receptor Binding Proteins).

Generation and Screening of Anti-PAC1 Receptor Antibodies.

Monoclonal anti-human PAC1 receptor antibodies were generated andsequenced as described in WO2014/144632 (Human PAC1 Antibodies), whichis hereby incorporated by reference in its entirety. Briefly, antibodieswere generated through immunization of XENOMOUSE® animals with the PAC1extracellular domain protein (DNA tagged with a T-cell epitope tag),L1.2 cells expressing full-length human PAC1, or other human PAC1antigens using standard methods, e.g., such as those detailed in USPatent Publication No. 2010/0172895. Hybridoma supernatants werescreened for binding to PAC1 receptor as well as for functionalantagonist activity in an assay detecting their ability to blockgeneration of cAMP by activation of PAC1 with either PACAP (e.g.,PACAP-27 or PACAP-38) or a selective, exogenous peptide ligand(Maxadilan), and then counter-screened against the related receptorsVPAC1 and VPAC2. Those supernatants with desirable function andselectivity were sequenced and cloned, expressed recombinantly,purified, and tested again for function and selectivity using standardmethods. Selected human PAC1 receptor antibodies were screened in an invitro PAC1-mediated cAMP assay to determine intrinsic potency. The assayemployed cell lines expressing human PAC1 (SH-SY-5Y, a humanneuroblastoma cell line endogenously expressing PAC1), cynomolgus PACi1, rat PAC i1, human VPAC1 and human VPAC2. The LANCE cAMP assay kit(PerkinElmer, Boston, Mass.) was used in the screening. The assays wereperformed in white 96-well plates in a total volume of 60 μL. Briefly,on the day of the assay, the frozen cells were thawed at 37° C., cellswere washed once with assay buffer and 12 μL of cell suspensioncontaining 10,000 cells mixed with Alexa-labeled anti-cAMP antibody wasadded into 96 half-area white plates. After adding 12 μL PAC1 antibody,the mixture was incubated for 30 min at room temperature. Then 12 μLPAC1 agonist PACAP-38 (1 nM final concentration) was added and furtherincubated for 15 min at room temperature. After agonist stimulation, 24μL of detection mix was added and incubated for 60 minutes at roomtemperature and the plates were read on EnVision instrument(PerkinElmer, Boston, Mass.) at an emission wavelength of 665 nM. Datawere processed and analyzed by Prizm (GraphPad Software Inc.) orActivityBase (IDBS).

Engineering to Improve Biophysical Properties

Of the monoclonal antibodies generated and screened as described above,a subset of the anti-CGRP receptor antibodies and anti-human PAC1receptor antibodies were identified for bispecific antibody generationand for engineering to improve biophysical properties.

Two antibodies were selected for optimization during the PAC1 antibodyengineering. These antibodies resulted from the novel CDR graftingexercise to improve sequence diversity, stability, and expression.However, the other PAC1 receptor antibodies and all of the CGRP receptorantibodies did not go through the optimization engineering process.However, these antibodies were analyzed for potential chemical hotspotsand covariance violations. It has been shown in numerous projects thatfixing the covariance violations improves the thermal stability,expression and biophysical properties of the antibodies. See, e.g.,WO2012/125495. Co-variance analysis was conducted of the selectedanti-CGRP receptor and anti-PAC1 receptor antibodies according to themethods described in WO2012/125495.

Example 2. Generation of CGRP Receptor/PAC1 Receptor HeteroImmunoglobulins

Generation of a bispecific antibody through co-expression of twodifferent antibodies leads to contaminants. The preferred bispecific,heterotetramer molecule with two different heavy chains associated withcorrectly paired light chains is only a minority of the total amount ofcombinations expressed. The contaminants occur mainly due to twodifferent reasons. The first reason is that the heavy chain that comestogether at the Fc region of the antibody can homodimerize, leading toconventional monospecific antibody, or heterodimerize, leading tobispecific antibody. The second reason is that light chain ispromiscuous and can pair with either of the heavy chains, leading tomispaired light-heavy chain Fab assembly that may not retain theactivity and binding to the desired target. Hence, the bispecificengineering is a two-step process. The first goal is to prevent thehomodimerization of the heavy chains and encourage heterodimerization.This can be achieved through engineering the Fc region of theantibodies, using, for example, the knobs-into-holes or charge pairmutations strategies. The second goal is to engineer the light-heavychain interface in such a way that the light chain is specificallyassociated only with its cognate heavy chain.

The “Hetero-Ig” platform technology (see, e.g., WO2009089004 andWO2014081955, both of which are hereby incorporated by reference intheir entireties) takes advantage of the electrostatic steeringmechanism to overcome the two problems mentioned above. Specifically,charged residues are introduced or exploited to drive heavy chainheterodimerization and light-heavy chain association. The charge pairmutations (CPMs) in the CH3 domain of the Fc region drive theheterodimerization of the two different heavy chains through oppositecharges that cause electrostatic attraction (see, e.g., WO2009089004 andU.S. Pat. No. 8,592,562); the two identical heavy chain combinationshave identical charges and are therefore repelled. The correct heavychain-light chain pairing is facilitated by CPMs at the CH1/CL bindinginterface (see FIG. 1; “v1” & “v4”) or between the VH/VL and CH1/CLbinding interfaces (see FIG. 1; “v3”). The correct heavy chain-lightchain combinations will have opposite charges and therefore be attractedto each other, whereas the incorrect heavy chain-light chaincombinations will have the same charges and be repelled. As a result,the correctly assembled hetero-Ig will have either three (“v1”) or fourCPMs (“v3” and “v4”) that drive the assembly of the preferredheterotetramer comprising two different heavy chains and two differentlight chains so that the heterotetramer will be the majority componentgenerated by the expression system.

Because the CGRP receptor and PAC1 receptor targets are expressed oncell surfaces, there is a risk of in vivo platelet depletion byantagonizing either target. Thus, the effector functionless IgG1scaffold (see, e.g., U.S. Patent Publication No. 2014/0343252, which ishereby incorporated by reference in its entirety) was chosen as theframework for the generation of the bispecific hetero Ig molecules. Theeffector functionless scaffold includes an IgG1 variant with a N297Gmutation to knock out the glycosylation in the CH2 domain and anengineered disulfide bond introduced in the CH2 domain to improve thestability in the absence of glycosylation. The lack of glycosylation inthe CH2 domain resulting from the N297G mutation leads to significantlyreduced binding to Fc gamma receptors, which helps address the plateletdepletion issue. See, e.g., Example 5 of WO2014/144632.

Six anti-PAC1 receptor antibodies (antibodies 01 to 06 as describedherein) and nine anti-CGRP receptor engineered antibodies (antibodies 50to 58 as described herein), with their co-variance violations corrected,were utilized to generate 169 distinct bispecific hetero Ig moleculesusing high throughput cloning, expression and purification. Each of thebispecific hetero Ig molecules had one of the three formats shown inFIG. 1 using the IgG1 effector functionless scaffold or an IgG2scaffold. The sequences of each of the 169 bispecific heteroimmunoglobulins are set forth in Table 8.

Example 3. Functional Activity of Bispecific Hetero ImmunoglobulinMolecules

The bispecific hetero Ig molecules generated as described in Example 2were tested for their ability to inhibit ligand-induced activation ofthe human CGRP receptor and the human PAC1 receptor using in vitro cAMPassays as described in detail below.

CGRP Receptor Activity Assay.

The assay employed a human neuroblastoma-derived cell line (SK-N-MC;Spengler, et al., (1973) In Vitro 8: 410) obtained from ATCC (ATCCNumber HTB-10; “HTB-10 cells”). HTB-10 cells express human CRLR andhuman RAMP1, which form the human CGRP receptor (McLatchie et al.,(1998) Nature, 393:333-339).

The LANCE Ultra cAMP assay kit (PerkinElmer, Boston, Mass.) was used.The assays were performed in white 96-well plates in a total volume of40 μL. Briefly, on the day of the assay, the frozen HTB-10 cells werethawed at 37° C. and were washed once with assay buffer. 10 L of cellsuspension containing 1000 cells was added into 96 half-area whiteplates. After adding 5 μL of the bispecific hetero IgG (single point or10 points dose response curve: final concentration ranges from 1 μM to0.5 μM), the mixture was incubated for 30 min at room temperature. Then,5 μL CGRP receptor agonist human α-CGRP (3 nM final concentration) wasadded and further incubated for 15 min at room temperature. After humanα-CGRP stimulation, L of detection mix was added and incubated for 45minutes at room temperature and the plates were read on EnVisioninstrument (PerkinElmer, Boston, Mass.) at an emission wavelength of 665nm. Data were processed and analyzed by Prizm (GraphPad Software Inc.).

PAC1 Receptor Activity Assay.

The assay employed a human neuroblastoma-derived cell line (SH-SH5Y;Biedler J L, et al., Cancer Res. 38: 3751-3757, 1978) obtained from ATCC(ATCC Number CRL-2266; “CRL-2266 cells”). CRL-2266 cells express humanPAC1 receptor (Monaghan et al., J Neurochem. 104(1): 74-88, 2008).

The LANCE Ultra cAMP assay kit (PerkinElmer, Boston, Mass.) was used.The assays were performed in white 96-well plates in a total volume of40 μL. Briefly, on the day of the assay, the frozen CRL-2266 cells werethawed at 37° C. and were washed once with assay buffer. 10 μL of cellsuspension containing 2000 cells was added into 96 half-area whiteplates. After adding 5 μL of the bispecific hetero IgG (single point or10 point dose response curve: concentration ranges from 1 μM to 0.5 μM,the mixture was incubated for 30 min at room temperature. Then, 5 μLPAC1 receptor agonist human PACAP38 (10 pM final concentration) wasadded and the mixture was further incubated for 15 min at roomtemperature. After human PACAP38 stimulation, 20 μL of detection mix wasadded and incubated for 45 minutes at room temperature and the plateswere read on EnVision instrument (PerkinElmer, Boston, Mass.) atemission wavelength 665 nm. Data were processed and analyzed by Prizm(GraphPad Software Inc.).

Percentage inhibition of CGRP receptor and PAC1 receptor activities foreach of the 169 bispecific hetero IgGs are shown in Table 15 below. IC50values were calculated for a subset of the bispecific hetero IgGs basedon a 10 point dose response curve. These IC50 values are shown below inTable 16.

TABLE 15 Percentage inhibition of human CGRP receptor and human PAC1receptor activity by bispecific hetero IgGs (n = 1) BispecificBispecific Hetero IgG % inhibition of % inhibition of Hetero IgG %inhibition of % inhibition of Designation human CGRPR human PAC1Designation human CGRPR human PAC1 iPS:326417 66 48 iPS:326651 66 23iPS:326626 96 86 iPS:326654 79 99 iPS:326628 84 61 iPS:328000 75 63iPS:326631 89 79 iPS:328001 65 95 iPS:326634 66 43 iPS:326661 77 72iPS:327870 67 86 iPS:326663 64 62 iPS:327871 65 68 iPS:326666 74 15iPS:326645 67 59 iPS:326669 74 85 iPS:326648 73 92 iPS:327017 67 27iPS:327018 68 17 iPS:327026 81 78 iPS:327019 65 79 iPS:327091 65 67iPS:327023 74 32 iPS:327092 73 52 iPS:327024 75 7 iPS:327093 70 68iPS:327025 76 21 iPS:327094 73 91 iPS:326414 70 58 iPS:327106 71 6iPS:327102 74 47 iPS:327107 76 22 iPS:327103 82 21 iPS:327108 66 74iPS:327104 81 95 iPS:327109 73 82 iPS:327105 81 63 iPS:327110 80 71iPS:327111 88 65 iPS:327270 71 82 iPS:327112 84 104 iPS:327272 81 62iPS:327267 75 29 iPS:327273 81 10 iPS:327268 79 38 iPS:327274 87 22iPS:327269 79 8 iPS:327275 85 86 iPS:327276 80 87 iPS:327282 87 58iPS:327277 83 56 iPS:327283 85 99 iPS:327278 85 47 iPS:327284 77 25iPS:327279 73 95 iPS:327285 84 9 iPS:327280 80 83 iPS:327286 85 23iPS:327281 82 50 iPS:327287 86 71 iPS:327288 67 88 iPS:327679 86 23iPS:327289 72 75 iPS:327680 88 92 iPS:327290 70 60 iPS:327681 72 73iPS:327291 70 89 iPS:327682 75 12 iPS:327677 81 43 iPS:327683 70 30iPS:327678 84 43 iPS:327684 71 74 iPS:327685 86 85 iPS:327689 78 86iPS:327686 87 69 iPS:327690 80 50 iPS:327687 91 62 iPS:327691 73 25iPS:327688 89 103 iPS:327693 76 82 iPS:327694 87 75 iPS:327705 88 56iPS:327696 87 10 iPS:327706 87 103 iPS:327697 88 39 iPS:327707 73 72iPS:327698 90 96 iPS:327708 79 18 iPS:327699 72 92 iPS:327709 82 29iPS:327700 77 72 iPS:327710 82 61 iPS:327701 73 41 iPS:327711 87 97iPS:327702 79 86 iPS:327712 89 81 iPS:327703 83 87 iPS:327713 89 85iPS:327704 82 71 iPS:327714 94 104 iPS:327717 92 94 iPS:327729 84 85iPS:327718 78 70 iPS:327730 87 101 iPS:327719 85 59 iPS:327731 74 74iPS:327721 81 99 iPS:327732 69 56 iPS:327722 82 38 iPS:327733 84 66iPS:327724 80 33 iPS:327734 82 99 iPS:327725 86 39 iPS:327735 81 68iPS:327726 91 77 iPS:327736 88 20 iPS:327727 93 93 iPS:327737 82 54iPS:327728 80 79 iPS:327738 85 93 iPS:327739 79 76 iPS:327875 83 10iPS:327740 74 58 iPS:327876 77 11 iPS:327741 83 70 iPS:327877 72 22iPS:327742 84 96 iPS:327878 75 42 iPS:327872 80 40 iPS:327879 81 19iPS:327874 95 5 iPS:327880 87 15 iPS:327881 76 16 iPS:327891 80 78iPS:327882 83 13 iPS:327892 88 33 iPS:327883 77 27 iPS:327893 74 56iPS:327884 78 8 iPS:327894 80 12 iPS:327885 73 7 iPS:327895 80 15iPS:327886 72 65 iPS:327896 87 28 iPS:327887 87 35 iPS:327897 80 12iPS:327888 83 56 iPS:328031 75 27 iPS:327889 83 9 iPS:328033 82 20iPS:327890 94 15 iPS:328034 86 9 iPS:328035 73 10 iPS:328041 82 17iPS:328036 79 21 iPS:328042 85 20 iPS:328037 71 25 iPS:328043 75 8iPS:328038 69 6 iPS:328044 77 5 iPS:328039 74 9 iPS:328045 67 29iPS:328040 74 70 iPS:328046 73 3 iPS:328047 78 33 iPS:328050 80 11iPS:328048 69 9 iPS:328051 77 21 iPS:328049 92 13

TABLE 16 Inhibitory activity of bispecific hetero IgGs against the humanCGRP receptor and human PAC1 receptor (n = 5, except where noted) HumanCGRP Human PAC1 Receptor Receptor Bispecific Hetero IgG IC50 (nM) ± IC50(nM) ± Designation SD SD iPS:326648 2.6 ± 0.8  2.7 ± 0.8 iPS:327026 5.5(n = 1) 5.4 (n = 1) iPS:327111 2.2 ± 0.8 19.4 ± 5.0 iPS:327112 10.1 (n =1)  13.6 (n = 1)  iPS:327270  1.9 ± 0.55 16.2 ± 4.2 iPS:327272 1.2 ± 0.7 48.7 ± 14.2 iPS:327283 12.9 (n = 1)  2.1 (n = 1) iPS:327680 2.0 ± 0.611.6 ± 4.3 iPS:327688 8.2 (n = 1) 7.1 (n = 1) iPS:327689 1.0 ± 0.5 13.6± 4.2 iPS:327698 1.6 ± 0.7 14.5 ± 2.0 iPS:327702  1.4 ± 0.48  6.7 ± 0.2iPS:327714 9.1 (n = 1) 2.6 (n = 1) iPS:327717  1.8 ± 0.76 20.2 ± 5.3iPS:327730 2.6 ± 1.3 12.2 ± 2.9 iPS:327741 1.9 ± 0.8 107.5 ± 30.5iPS:327742 1.4 ± 0.6 11.1 ± 3.5 iPS:328001 2.5 ± 1.1  2.8 ± 1.0

Example 4. Synthesis and Activity of CGRP Receptor/PAC1 ReceptorIgG-scFv Bispecific Antigen Binding Proteins

A subset of the anti-CGRP receptor and anti-PAC1 receptor antibodiesdescribed in Example 1 were used to design bispecific antigen bindingproteins having an IgG-scFv format. In this format, a single-chainvariable fragment (scFv) containing heavy and light chain variabledomains from a first antibody is fused through a peptide linker to thecarboxyl-terminus of the heavy chain of a second antibody to form amodified heavy chain (see FIG. 2). The light chain from the secondantibody is expressed with the modified heavy chain. Assembly of thefull molecule creates a tetravalent binding protein having two antigenbinding domains against a first target located on the amino terminalside of a dimerized immunoglobulin Fc region and two antigen bindingdomains against a second target located on the carboxyl terminal side ofthe dimerized Fc region.

The CGRPR/PAC1 IgG-scFv contains two antigen binding domains, onedirected against CGRP receptor and the other against PAC1 receptor. TheDNA molecules encoding CGRPR-PAC1 IgG-scFv molecules contain fragmentscoding for an anti-CGRPR (or anti-PAC1 receptor) antibody heavy chain(HC) in which the C-terminus is fused to an anti-PAC1 receptor (oranti-CGRP receptor) single chain variable fragment (scFv) with orwithout cysteine clamp, and an anti-CGRP receptor (or anti-PAC1receptor) antibody light chain (LC). In order to introduce the cysteineclamp, which can improve stability, position 44 (Kabat numbering) in theVH region and position 100 (Kabat numbering) in the VL region weremutated to cysteine. The DNA molecules were generated by synthesizedgBlocks and cloned into a pTT5.1 vector. These expression vectors wereused to transfect and express the CGRPR/PAC1 bispecific molecules inhuman 293-6E cells. Thirty different IgG-scFv bispecific molecules weregenerated. The full sequences for each molecule are set forth in Table9.

The IgG-scFv molecules were tested for their ability to inhibitligand-induced activation of the human CGRP receptor and the human PAC1receptor using in vitro cAMP assays as described in Example 3. IC50values for each of the molecules for each target receptor are shown inTable 17 below.

TABLE 17 Inhibitory activity of bispecific IgG-scFv molecules againstthe human CGRP receptor and human PAC1 receptor Human CGRP Human PAC1Bispecific IgG-scFv Receptor Receptor Designation IC50 (nM) IC50 (nM)iPS:386705 0.43 605.28 iPS:386707 0.47 739.75 iPS:386709 0.47 431.70iPS:386711 0.53 1211.80 iPS:386713 0.37 603.02 iPS:386725 0.42 548.93iPS:386727 0.72 371.35 iPS:386729 0.47 565.33 iPS:386731 0.40 346.93iPS:386733 0.34 74.33 iPS:386736 0.90 5.43 iPS:386738 0.74 5.09iPS:386740 0.56 4.40 iPS:386742 0.61 6.39 iPS:386744 0.61 3.63iPS:386746 0.79 3.28 iPS:386748 0.63 2.85 iPS:386750 0.58 4.54iPS:386752 0.62 6.08 iPS:386754 0.54 5.74 iPS:386756 1.88 7.29iPS:386758 2.32 4.11 iPS:386760 2.11 4.67 iPS:386762 2.80 3.55iPS:386764 2.61 11.88 iPS:386715 0.43 688.60 iPS:386717 0.33 580.08iPS:386719 0.41 940.48 iPS:386721 0.22 197.13 iPS:386723 0.27 248.18

All bispecific IgG-scFv molecules tested exhibited inhibitory activityagainst both human CGRP receptor and human PAC1 receptor. Interestingly,the molecules that were the more potent inhibitors of the PAC1 receptor(e.g., iPS:386736, iPS:386738, iPS:386740, iPS:386742, iPS:386744,iPS:386746, iPS:386748, iPS:386750, iPS:386752, iPS:386754, iPS:386756,iPS:386758, iPS:386760, iPS:386762, and iPS:386764) were those in whichthe PAC1 receptor binding domain was located at the amino terminus ofthe Fc region. Generally, in this format, the CGRP receptor bindingdomain could be located on either side of the Fc region withoutsubstantially affecting inhibitory potency.

Example 5. Synthesis and Activity of CGRP Receptor/PAC1 Receptor IgG-FabBispecific Antigen Binding Proteins

Additional bispecific antigen binding proteins were prepared with asubset of the anti-CGRP receptor and anti-PAC1 receptor antibodiesdescribed in Example 1 using a third format.

In some embodiments of this IgG-Fab format, a polypeptide comprisingeither VL-CL domains or VH-CH1 domains from a first antibody is fusedthrough a peptide linker to the carboxyl-terminus of the heavy chain ofa second antibody to form a modified heavy chain (see FIG. 3).

A second polypeptide comprising the remaining domains of the Fabfragment from the first antibody (i.e. VH-CH1 domains or VL-CL domains)is co-expressed with the light chain of the second antibody and themodified heavy chain to produce the complete molecule. Similar to theIgG-scFv format, assembly of the full molecule creates a tetravalentbinding protein having two antigen binding domains against a firsttarget located on the amino terminal side of a dimerized immunoglobulinFc region and two antigen binding domains against a second targetlocated on the carboxyl terminal side of the dimerized Fc region.

The CGRPR/PAC1 IgG-Fab consists of two antigen binding domains, onedirected against the CGRP receptor and the other against the PAC1receptor. The DNA molecules encoding CGRPR-PAC1 IgG-Fab moleculescontain fragments encoding an anti-CGRP receptor (or anti-PAC1 receptor)antibody light chain, an anti-CGRP receptor (or anti-PAC1 receptor)antibody heavy chain in which the C-terminus is fused to (i) ananti-PAC1 receptor (or anti-CGRP receptor) antibody light chain or (ii)an anti-PAC1 receptor (or anti-CGRP receptor) Fd (VH-CH1), and a thirdpolypeptide comprising the other half of the Fab fragment to completethe carboxy-terminal binding domain (e.g. (i) an anti-PAC1 receptor (oranti-CGRP receptor) Fd or (ii) an anti-PAC1 receptor (or anti-CGRPreceptor) antibody light chain. The IgG-Fab bispecific molecules containcharge pair mutations introduced into CH1 and CL domains of each Fabregion (Fab 1 and Fab 2 as illustrated in FIG. 3). The charge pairs aredesigned to allow preferential assembly of anti-CGRPR lightchain/VHCH1(Fd) pair and anti-PAC1 light chain/VHCH1 (Fd) pair. As anadditional approach to promote correct pairing of the light chain/VHCH1(Fd) pair, for a subset of the IgG-Fab molecules generated, the CL andCH1 regions in the carboxyl-terminal Fab (i.e. Fab 2) were swapped suchthat the polypeptide fused to the carboxyl-terminal region of the heavychain of the second antibody comprised VL and CH1 regions from the firstantibody and the second polypeptide comprised VH and CL regions from thefirst antibody. See molecules designated iPS:392513, iPS:392514,iPS:392475, iPS: 392519, iPS:392524, iPS:392525, iPS:392526, and iPS:392527 in Table 10. The DNA molecules were generated by synthesizedgBlocks and cloned into the pTT5.1 vector. These expression vectors wereused to transfect and express the CGRPR/PAC1 bispecific molecules inhuman 293 6E cells. Twenty four different IgG-Fab bispecific moleculeswere generated. The full sequences for each molecule are set forth inTable 10.

The IgG-Fab molecules were tested for their ability to inhibitligand-induced activation of the human CGRP receptor and the human PAC1receptor using in vitro cAMP assays as described in Example 3. IC50values for each of the molecules for each target receptor are shown inTable 18 below.

TABLE 18 Inhibitory activity of bispecific IgG-Fab molecules against thehuman CGRP receptor and human PAC1 receptor Human CGRP Human PAC1Bispecific IgG-Fab Receptor Receptor Designation IC50 (nM) IC50 (nM)iPS:392475 20.44 4.78 iPS:392513 60.16 2.70 iPS:392514 53.95 4.69iPS:392515 12.90 2.66 iPS:392516 27.85 9.30 iPS:392517 - lot #1 10.892.48 iPS:392517 - lot #2 11.48 7.75 iPS:392518 17.75 3.40 iPS:39251981.28 6.87 iPS:392520 10.50 6.28 iPS:392521 18.76 6.88 iPS:392522 - lot#1 8.80 9.32 iPS:392522 - lot #2 7.58 3.29 iPS:392523 20.38 5.03iPS:392524 0.86 81.20 iPS:392525 1.22 37.14 iPS:392526 0.71 115.58iPS:392527 0.42 16.40 iPS:392528 0.55 >1000 iPS:392529 0.56 >1000iPS:392530 0.38 >1000 iPS:392531 0.42 >1000 iPS:392532 0.51 352.50iPS:392533 0.59 205.80 iPS:392534 0.37 349.20 iPS:392535 0.41 365.03

All but four of the bispecific IgG-Fab molecules tested exhibitedinhibitory activity against both receptors.

All publications, patents, and patent applications discussed and citedherein are hereby incorporated by reference in their entireties. It isunderstood that the disclosed invention is not limited to the particularmethodology, protocols and materials described as these can vary. It isalso understood that the terminology used herein is for the purposes ofdescribing particular embodiments only and is not intended to limit thescope of the appended claims.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed:
 1. A bispecific antigen binding protein comprising afirst binding domain that specifically binds to human CGRP receptor anda second binding domain that specifically binds to human PAC1 receptorat an epitope within the amino-terminal extracellular domain defined byamino acids 21 to 155 of SEQ ID NO: 339, wherein the first bindingdomain comprises a first light chain immunoglobulin variable region(VL1) and a first heavy chain immunoglobulin variable region (VH1), andthe second binding domain comprises a second light chain immunoglobulinvariable region (VL2) and a second heavy chain immunoglobulin variableregion (VH2), and wherein VL2 comprises (i) a CDRL1 selected from SEQ IDNOs: 1 to 13, (ii) a CDRL2 selected from SEQ ID NOs: 14 to 19, and (iii)a CDRL3 selected from SEQ ID NOs: 20 to 27, and wherein VH2 comprises(i) a CDRH1 selected from SEQ ID NOs: 55 to 65, (ii) a CDRH2 selectedfrom SEQ ID NOs: 66 to 73, and (iii) a CDRH3 selected from SEQ ID NOs:74 to
 82. 2. The bispecific antigen binding protein of claim 1, whereinVL1 comprises (i) a CDRL1 selected from SEQ ID NOs: 109 to 119, (ii) aCDRL2 selected from SEQ ID NOs: 14, 17, 18, and 120 to 126, and (iii) aCDRL3 selected from SEQ ID NOs: 127 to 135, and wherein VH1 comprises(i) a CDRH1 selected from SEQ ID NOs: 159 to 166, (ii) a CDRH2 selectedfrom SEQ ID NOs: 167 to 178, and (iii) a CDRH3 selected from SEQ ID NOs:179 to
 189. 3. The bispecific antigen binding protein of claim 2,wherein VL1 comprises a sequence that is at least 90% identical to anamino acid sequence selected from SEQ ID NOs: 136 to 158, and whereinVH1 comprises a sequence that is at least 90% identical to an amino acidsequence selected from SEQ ID NOs: 190 to
 210. 4. The bispecific antigenbinding protein of claim 1, wherein VL1 comprises a CDRL1, a CDRL2, anda CDRL3, and VH1 comprises a CDRH1, a CDRH2, and a CDRH3, and wherein:(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 109, 120and 127, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence ofSEQ ID NOs: 159, 167 and 179, respectively; (b) CDRL1, CDRL2, and CDRL3have the sequence of SEQ ID NOs: 109, 120 and 127, respectively, andCDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 159, 168 and179, respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQID NOs: 110, 121 and 128, respectively, and CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 160, 169 and 180, respectively; (d) CDRL1,CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 110, 121 and 128,respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 160, 169 and 181, respectively; (e) CDRL1, CDRL2, and CDRL3 havethe sequence of SEQ ID NOs: 111, 17 and 129, respectively, and CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 161, 170 and 182,respectively; or (f) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ IDNOs: 111, 17 and 129, respectively, and CDRH1, CDRH2, and CDRH3 have thesequence of SEQ ID NOs: 161, 171 and 182, respectively.
 5. Thebispecific antigen binding protein of claim 1, wherein: (a) VL1comprises the sequence of SEQ ID NO: 136 and VH1 comprises the sequenceof SEQ ID NO: 190; (b) VL1 comprises the sequence of SEQ ID NO: 138 andVH1 comprises the sequence of SEQ ID NO: 192; (c) VL1 comprises thesequence of SEQ ID NO: 140 and VH1 comprises the sequence of SEQ ID NO:194; (d) VL1 comprises the sequence of SEQ ID NO: 140 and VH1 comprisesthe sequence of SEQ ID NO: 196; (e) VL1 comprises the sequence of SEQ IDNO: 142 and VH1 comprises the sequence of SEQ ID NO: 194; (f) VL1comprises the sequence of SEQ ID NO: 142 and VH1 comprises the sequenceof SEQ ID NO: 196; (g) VL1 comprises the sequence of SEQ ID NO: 144 andVH1 comprises the sequence of SEQ ID NO: 194; (h) VL1 comprises thesequence of SEQ ID NO: 146 and VH1 comprises the sequence of SEQ ID NO:198; or (i) VL1 comprises the sequence of SEQ ID NO: 146 and VH1comprises the sequence of SEQ ID NO:
 200. 6. The bispecific antigenbinding protein of claim 1, wherein: (a) CDRL1, CDRL2, and CDRL3 of VL2have the sequence of SEQ ID NOs: 1, 14 and 20, respectively, and CDRH1,CDRH2, and CDRH3 of VH2 have the sequence of SEQ ID NOs: 55, 66 and 74,respectively; (b) CDRL1, CDRL2, and CDRL3 of VL2 have the sequence ofSEQ ID NOs: 2, 15 and 21, respectively, and CDRH1, CDRH2, and CDRH3 ofVH2 have the sequence of SEQ ID NOs: 56, 67 and 75, respectively; (c)CDRL1, CDRL2, and CDRL3 of VL2 have the sequence of SEQ ID NOs: 3, 15and 21, respectively, and CDRH1, CDRH2, and CDRH3 of VH2 have thesequence of SEQ ID NOs: 56, 67 and 75, respectively; or (d) CDRL1,CDRL2, and CDRL3 of VL2 have the sequence of SEQ ID NOs: 4, 16 and 22,respectively, and CDRH1, CDRH2, and CDRH3 of VH2 have the sequence ofSEQ ID NOs: 57, 68 and 76, respectively.
 7. The bispecific antigenbinding protein of claim 1, wherein VL2 comprises a sequence that is atleast 90% identical to an amino acid sequence selected from SEQ ID NOs:28 to 54, and wherein VH2 comprises a sequence that is at least 90%identical to an amino acid sequence selected from SEQ ID NOs: 83 to 108.8. The bispecific antigen binding protein of claim 1, wherein: (a) VL2comprises the sequence of SEQ ID NO: 28 and VH2 comprises the sequenceof SEQ ID NO: 83; (b) VL2 comprises the sequence of SEQ ID NO: 30 andVH2 comprises the sequence of SEQ ID NO: 83; (c) VL2 comprises thesequence of SEQ ID NO: 31 and VH2 comprises the sequence of SEQ ID NO:85; (d) VL2 comprises the sequence of SEQ ID NO: 33 and VH2 comprisesthe sequence of SEQ ID NO: 87; (e) VL2 comprises the sequence of SEQ IDNO: 35 and VH2 comprises the sequence of SEQ ID NO: 89; or (f) VL2comprises the sequence of SEQ ID NO: 37 and VH2 comprises the sequenceof SEQ ID NO:
 91. 9. The bispecific antigen binding protein of claim 1,wherein the first binding domain and/or the second binding domaincomprise a Fab fragment, a Fab′ fragment, a F(ab′)₂ fragment, a Fvfragment, or a single-chain variable fragment (scFv).
 10. The bispecificantigen binding protein of claim 1, wherein the binding proteincomprises a constant region from an IgG1, IgG2, IgG3, or IgG4immunoglobulin.
 11. The bispecific antigen binding protein of claim 10,wherein the constant region comprises human IgG1 or IgG2 immunoglobulinCH2 and CH3 domains.
 12. The bispecific antigen binding protein of claim1, wherein the binding protein is an antibody.
 13. The bispecificantigen binding protein of claim 12, wherein the antibody comprises afirst light chain (LC1) and a first heavy chain (HC1) from a firstantibody that specifically binds to human CGRP receptor and a secondlight chain (LC2) and second heavy chain (HC2) from a second antibodythat specifically binds to human PAC1 receptor.
 14. The bispecificantigen binding protein of claim 13, wherein LC1 comprises a sequenceselected from SEQ ID NOs: 271 to 282, and wherein HC1 comprises asequence selected from SEQ ID NOs: 295 to
 316. 15. The bispecificantigen binding protein of claim 13, wherein LC2 comprises a sequenceselected from SEQ ID NOs: 211 to 221, and wherein HC2 comprises asequence selected from SEQ ID NOs: 233 to
 251. 16. The bispecificantigen binding protein of claim 13, wherein: (a) LC1 comprises thesequence of SEQ ID NO: 271 and HC1 comprises the sequence of SEQ ID NO:295, SEQ ID NO: 297, or SEQ ID NO: 298; (b) LC1 comprises the sequenceof SEQ ID NO: 272 and HC1 comprises the sequence of SEQ ID NO: 296; (c)LC1 comprises the sequence of SEQ ID NO: 273 and HC1 comprises thesequence of SEQ ID NO: 299, SEQ ID NO: 301, or SEQ ID NO: 302; (d) LC1comprises the sequence of SEQ ID NO: 274 and HC1 comprises the sequenceof SEQ ID NO: 300; (e) LC1 comprises the sequence of SEQ ID NO: 275 andHC1 comprises the sequence of SEQ ID NO: 303, SEQ ID NO: 305, SEQ ID NO:306, SEQ ID NO: 307, or SEQ ID NO: 309; (f) LC1 comprises the sequenceof SEQ ID NO: 276 and HC1 comprises the sequence of SEQ ID NO: 304 orSEQ ID NO: 308; (g) LC1 comprises the sequence of SEQ ID NO: 277 and HC1comprises the sequence of SEQ ID NO: 303, SEQ ID NO: 305, SEQ ID NO:307, or SEQ ID NO: 309; (h) LC1 comprises the sequence of SEQ ID NO: 278and HC1 comprises the sequence of SEQ ID NO: 304 or SEQ ID NO: 308; (i)LC1 comprises the sequence of SEQ ID NO: 279 and HC1 comprises thesequence of SEQ ID NO: 303 or SEQ ID NO: 305; (j) LC1 comprises thesequence of SEQ ID NO: 280 and HC1 comprises the sequence of SEQ ID NO:304; (k) LC1 comprises the sequence of SEQ ID NO: 281 and HC1 comprisesthe sequence of SEQ ID NO: 310, SEQ ID NO: 312, SEQ ID NO: 313, SEQ IDNO: 314, or SEQ ID NO: 316; or (l) LC1 comprises the sequence of SEQ IDNO: 282 and HC1 comprises the sequence of SEQ ID NO: 311 or SEQ ID NO:315.
 17. The bispecific antigen binding protein of claim 16, wherein:(a) LC2 comprises the sequence of SEQ ID NO: 211 and HC2 comprises thesequence of SEQ ID NO: 233, SEQ ID NO: 235, or SEQ ID NO: 236; (b) LC2comprises the sequence of SEQ ID NO: 212 and HC2 comprises the sequenceof SEQ ID NO: 234; (c) LC2 comprises the sequence of SEQ ID NO: 214 andHC2 comprises the sequence of SEQ ID NO: 237, SEQ ID NO: 239, or SEQ IDNO: 240; (d) LC2 comprises the sequence of SEQ ID NO: 215 and HC2comprises the sequence of SEQ ID NO: 238; (e) LC2 comprises the sequenceof SEQ ID NO: 216 and HC2 comprises the sequence of SEQ ID NO: 241, SEQID NO: 243, or SEQ ID NO: 244; or (f) LC2 comprises the sequence of SEQID NO: 217 and HC2 comprises the sequence of SEQ ID NO:
 242. 18. Thebispecific antigen binding protein of claim 13, wherein LC1 comprisesthe sequence of SEQ ID NO: 275, HC1 comprises the sequence of SEQ ID NO:306, LC2 comprises the sequence of SEQ ID NO: 216, and HC2 comprises thesequence of SEQ ID NO:
 244. 19. The bispecific antigen binding proteinof claim 13, wherein LC1 comprises the sequence of SEQ ID NO: 277, HC1comprises the sequence of SEQ ID NO: 309, LC2 comprises the sequence ofSEQ ID NO: 216, and HC2 comprises the sequence of SEQ ID NO:
 243. 20.The bispecific antigen binding protein of claim 13, wherein LC1comprises the sequence of SEQ ID NO: 276, HC1 comprises the sequence ofSEQ ID NO: 308, LC2 comprises the sequence of SEQ ID NO: 217, and HC2comprises the sequence of SEQ ID NO:
 242. 21. The bispecific antigenbinding protein of claim 13, wherein LC1 comprises the sequence of SEQID NO: 281, HC1 comprises the sequence of SEQ ID NO: 314, LC2 comprisesthe sequence of SEQ ID NO: 216, and HC2 comprises the sequence of SEQ IDNO:
 241. 22. A pharmaceutical composition comprising the bispecificantigen binding protein of claim 13, and a pharmaceutically acceptablediluent, excipient or carrier.
 23. A method for treating headache in apatient in need thereof, comprising administering to the patient aneffective amount of the bispecific antigen binding protein of claim 13.24. The bispecific antigen binding protein of claim 12, wherein theantibody is selected from the antibodies designated as iPS:326417,iPS:326626, iPS:326628, iPS:326631, iPS:326634, iPS:327870, iPS:327871,iPS:326645, iPS:326648, iPS:326651, iPS:326654, iPS:328000, iPS:328001,iPS:326661, iPS:326663, iPS:326666, iPS:326669, iPS:327017, iPS:327018,iPS:327019, iPS:327023, iPS:327024, iPS:327025, iPS:327026, iPS:327091,iPS:327092, iPS:327093, iPS:327094, iPS:326414, iPS:327102, iPS:327103,iPS:327104, iPS:327105, iPS:327106, iPS:327107, iPS:327108, iPS:327109,iPS:327110, iPS:327111, iPS:327112, iPS:327267, iPS:327268, iPS:327269,iPS:327270, iPS:327272, iPS:327273, iPS:327274, iPS:327275, iPS:327276,iPS:327277, iPS:327278, iPS:327279, iPS:327280, iPS:327281, iPS:327282,iPS:327283, iPS:327284, iPS:327285, iPS:327286, iPS:327287, iPS:327288,iPS:327289, iPS:327290, iPS:327291, iPS:327677, iPS:327678, iPS:327679,iPS:327680, iPS:327681, iPS:327682, iPS:327683, iPS:327684, iPS:327685,iPS:327686, iPS:327687, iPS:327688, iPS:327689, iPS:327690, iPS:327691,iPS:327693, iPS:327694, iPS:327696, iPS:327697, iPS:327698, iPS:327699,iPS:327700, iPS:327701, iPS:327702, iPS:327703, iPS:327704, iPS:327705,iPS:327706, iPS:327707, iPS:327708, iPS:327709, iPS:327710, iPS:327711,iPS:327712, iPS:327713, iPS:327714, iPS:327717, iPS:327718, iPS:327719,iPS:327721, iPS:327722, iPS:327724, iPS:327725, iPS:327726, iPS:327727,iPS:327728, iPS:327729, iPS:327730, iPS:327731, iPS:327732, iPS:327733,iPS:327734, iPS:327735, iPS:327736, iPS:327737, iPS:327738, iPS:327739,iPS:327740, iPS:327741, iPS:327742, iPS:327872, iPS:327874, iPS:327875,iPS:327876, iPS:327877, iPS:327878, iPS:327879, iPS:327880, iPS:327881,iPS:327882, iPS:327883, iPS:327884, iPS:327885, iPS:327886, iPS:327887,iPS:327888, iPS:327889, iPS:327890, iPS:327891, iPS:327892, iPS:327893,iPS:327894, iPS:327895, iPS:327896, iPS:327897, iPS:328031, iPS:328033,iPS:328034, iPS:328035, iPS:328036, iPS:328037, iPS:328038, iPS:328039,iPS:328040, iPS:328041, iPS:328042, iPS:328043, iPS:328044, iPS:328045,iPS:328046, iPS:328047, iPS:328048, iPS:328049, iPS:328050, oriPS:328051 as set forth in Table
 8. 25. One or more isolated nucleicacids encoding the bispecific antigen binding protein of claim
 1. 26. Anexpression vector comprising the one or more isolated nucleic acids ofclaim
 25. 27. A cultured host cell comprising the vector of claim 26.28. A method for the preparation of a bispecific antigen bindingprotein, comprising: culturing the host cell of claim 27 underconditions that allow expression of the antigen binding protein; andrecovering the antigen binding protein from the culture.
 29. Apharmaceutical composition comprising the bispecific antigen bindingprotein of claim 1, and a pharmaceutically acceptable diluent, excipientor carrier.
 30. A method for treating headache in a patient in needthereof, comprising administering to the patient an effective amount ofthe bispecific antigen binding protein of claim
 1. 31. The bispecificantigen binding protein of claim 1, wherein the binding proteincomprises: (i) the first binding domain that specifically binds to humanCGRP receptor; (ii) the second binding domain that specifically binds tohuman PAC1 receptor; and (iii) a human immunoglobulin Fc region, whereinone of the binding domains is positioned at the amino terminus of the Fcregion and the other binding domain is positioned at the carboxylterminus of the Fc region.
 32. The bispecific antigen binding protein ofclaim 31, wherein the carboxyl-terminal binding domain is a scFv and isfused at its amino terminus to the carboxyl terminus of the Fc regionthrough a peptide linker.
 33. The bispecific antigen binding protein ofclaim 32, wherein the variable regions are positioned in the scFv in aVH-VL or VL-VH orientation.
 34. The bispecific antigen binding proteinof claim 31, wherein the carboxyl-terminal binding domain is a Fab andis fused through a peptide linker to the carboxyl terminus of the Fcregion.
 35. The bispecific antigen binding protein of claim 34, whereinthe Fab is fused to the Fc region through the amino terminus of the VLregion of the Fab.
 36. The bispecific antigen binding protein of claim34, wherein the Fab is fused to the Fc region through the amino terminusof the VH region of the Fab.
 37. The bispecific antigen binding proteinof claim 31, wherein the amino-terminal binding domain is a Fab and isfused to the amino terminus of the Fc region through an immunoglobulinhinge region.
 38. The bispecific antigen binding protein of claim 37,wherein the amino-terminal Fab is fused to the Fc region through thecarboxyl terminus of the CH1 region of the Fab.
 39. The bispecificantigen binding protein of claim 31, wherein the first domain thatspecifically binds to human CGRP receptor is positioned at the aminoterminus of the Fc region and the second domain that specifically bindsto human PAC1 receptor is positioned at the carboxyl terminus of the Fcregion.
 40. The bispecific antigen binding protein of claim 31, whereinthe second domain that specifically binds to human PAC1 receptor ispositioned at the amino terminus of the Fc region and the first domainthat specifically binds to human CGRP receptor is positioned at thecarboxyl terminus of the Fc region.
 41. The bispecific antigen bindingprotein of claim 31, wherein the Fc region comprises a CH2 domain and aCH3 domain from a human IgG1 or IgG2 immunoglobulin.
 42. Apharmaceutical composition comprising the bispecific antigen bindingprotein of claim 31, and a pharmaceutically acceptable diluent,excipient or carrier.
 43. A method for treating headache in a patient inneed thereof, comprising administering to the patient an effectiveamount of the bispecific antigen binding protein of claim 31.